Processes For Making Lactose Utilizing Pre-Classification Techniques And Pharmaceutical Formulations Formed Therefrom

ABSTRACT

A process for forming lactose suitable for use in a pharmaceutical formulation comprises providing a plurality of lactose particles containing no more than 10% w/w of lactose particles having a volume average particle size of about 70 microns or less; milling the plurality of lactose particles to yield a plurality of milled lactose particles with an average particle size, (D50), ranging from about 50 microns to about 100 microns; and classifying the plurality of milled lactose particles into at least two fractions comprising a fine fraction and a coarse fraction wherein the fine fraction has an average particle size, (D50), ranging from about 3 microns to about 50 microns, and the coarse fraction has an average particle size, (D50), ranging from about 40 microns to about 250 microns.

FIELD OF THE INVENTION

The invention generally relates to processes for making lactose andpharmaceutical formulations formed therefrom.

BACKGROUND OF THE INVENTION

In the field of inhalation therapy, it is generally desirable to employtherapeutic molecules having a particle size (i.e., diameter) in therange of 1 to 10 μm. Carrier molecules or excipients, such as lactose,for inhaled therapeutic preparations also include significantly largerdiameter particles (e.g., 100 to 150 μm) that typically do not penetrateinto the upper respiratory tract to the same degree as the activeingredient. In general, it is preferable to use a smaller particle sizefor the lactose or a lactose blend having a defined ratio of coarse andfine lactose.

The lactose particle size and distribution will also, in many instances,significantly influence pharmaceutical and biological properties, suchas, for example, bioavailablity. For example, it is well known thatcoarse lactose in crystalline form has a fair flow rate and goodphysical stability whereas fine lactose powder, such as that produced byconventional fine grinding or milling, generally lacks good flowproperties. Lactose prepared by conventional spray drying either lacksdesired flow properties or contains too many large sized lactosecrystals.

It is well known that one particular drawback associated withconventional means of producing pharmaceutical grade lactose relates toundesirable variations in particle size, morphology and distribution.Such production methods are particularly problematic in that they oftenlead to excessive and undesirable variations in the fine particle mass(“FPMass”) of pharmaceutical formulations employing such lactose. FPMassis the weight of medicament within a given dose that reaches the desiredsize airways to be effective. For example, a desired size may be definedas approximately 1 micron to 10 microns as measured by laser scatteringtechniques.

Lactose morphology is believed to be another important parameter tocontrol, and it is believed that the degree of surface roughness caninfluence the interaction between the lactose particle and excipient andas such is now often measured as part of the lactose selection criteria.See e.g., Pharmaceutical Technology Europe April 2004, page 23.

It is possible that two lactose particles may be measured as having thesame particle size, but if one is smooth, eg un-milled crystallinelactose, and the other is a rougher-surfaced milled crystal, that thesecould associate to a different extent with the active and thus impactupon either the initial FPMass performance or the through life stabilityperformance of the product.

SUMMARY OF THE INVENTION

The present invention attempts to address the above problems associatedwith conventional processes of producing lactose, and provides a processof producing lactose possessing reduced levels of variation for bothparticle size distribution and particle morphology.

In one aspect, the invention provides a process for forming lactosesuitable for use in a pharmaceutical formulation and having apredetermined particle size distribution. The process comprisesproviding a plurality of lactose particles containing no more than 10%w/w of lactose particles having a volume average particle size of about70 microns or less; milling the plurality of lactose particles to yielda plurality of milled lactose particles with an average particle size,(D50), ranging from about 50 microns to about 100 microns; and thenclassifying the plurality of milled lactose particles into at least twofractions comprising a fine fraction and a coarse fraction wherein thefine fraction has an average particle size, (D50), ranging from about 3microns to about 50 microns, and the coarse fraction has an averageparticle size, (D50), ranging from about 40 microns to about 250microns. In one embodiment, appropriate amounts of coarse and finefractions may be combined with at least one medicament to form apharmaceutical formulation.

These and other aspects are encompassed by the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a particle size profile for lactose formed inaccordance with Example 1.

FIG. 2 illustrates a particle size profile for lactose formed inaccordance with Example 2.

FIG. 3 illustrates a particle size profile for lactose formed inaccordance with Example 3.

FIG. 4 illustrates a comparison of a particle size profile for lactoseformed in accordance with Example 2 with two conventional productionbatches.

FIG. 5 illustrates the particles size distribution of the initialcrystalline A feed lactose used in Examples 1, 2 and 3. This shows thevarying amounts of lactose in the less than 60 micron region.

FIG. 6 illustrates the particles size distribution of the crystalline Afeed lactose after it has been classified to remove the majority of thesmaller crystalline lactose particles.

FIG. 7 illustrates the correlation between D10 and the Span of FeedLactose Batches.

FIG. 8 illustrates the particle size distribution for pre-classifiedlactose, coarse fraction.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described with respect to the embodiments setforth herein. It should be appreciated that these embodiments are setforth to illustrate the invention, and that the invention is not limitedto these embodiments.

All publications, patents, and patent applications cited herein, whethersupra or infra, are hereby incorporated herein by reference in theirentirety to the same extent as if each individual publication, patent,or patent application was specifically and individually indicated to beincorporated by reference.

It must be noted that, as used in the specification and appended claims,the singular forms “a”, “an”, “one” and “the” may include pluralreferences unless the content clearly dictates otherwise.

As used herein, the term “D50” is defined as the size in microns aboveor below which 50 percent of the particles reside on a volume basis.

The process for forming lactose in accordance with the present inventionmay encompass various embodiments. For example, in one embodiment, thestep of milling the plurality of lactose particles to yield a pluralityof lactose particles may encompass obtaining those particles with anaverage particle size (D50) ranging from about 50, 55, 60, 65, 70 or 75microns to about 70, 75, 80, 85, 90, 95 or 100 microns. In oneembodiment, for example, the step of classifying the plurality of milledlactose particles into at least two fractions may result in a finefraction having an average particle size (D50) ranging from about 3, 10,15, 20, 25, 30 or 35 microns to about 30, 35, 40, 45 or 50 microns aswell as a coarse fraction having an average particle size (D50) rangingfrom about 40, 75, 100, 125 or 150 microns to about 100, 125, 150, 175,200, 225 or 250 microns, as measured by Malvern particle sizing.

In accordance with the present invention, the term “lactose” as usedherein is to be broadly construed. As an example, lactose is intended toencompass physical, crystalline, amorphous and polymorphic forms oflactose, including, but not limited to, the stereoisomers α-lactosemonohydrate and β-anhydrous lactose, as well as α-anhydrous lactose.Combinations of the above may be used.

Lactose (i.e., milk sugar) is preferably obtained from cheese whey,which can be manufactured in different forms depending on the processemployed. As used herein, the term “particle” is to be broadlyinterpreted to encompass those of various shapes, sizes, and/or textureswhich can include those that may have varying degrees of irregularities,disuniformities, etc. or which may possess regular and/or uniformproperties.

The plurality of lactose particles used in the process of the presentinvention may be acquired in various manners. In one embodiment, theplurality of lactose particles is present in the form of crystalline orunmilled lactose. In one embodiment, the initial step of providinglactose particles containing no more than 10% w/w of lactose particleshaving a volume average particle size of about 70 microns or less,comprises obtaining the plurality of lactose particles from acrystallization process. One example of a suitable crystallizationprocess that may be employed is set forth in copending U.S. Applicationentitled “Process for Crystallizing Lactose Particles for Use inPharmaceutical Formulations”, Ser. No. 60/651,754 filed concurrentlyherewith. It should be understood that other processes may also beemployed.

In another embodiment, the initial step of providing a plurality oflactose particles containing no more than 10% w/w of lactose particleshaving a volume average particle size of about 70 microns or less,comprises obtaining the plurality of lactose particles by sieving asource of lactose to produce the plurality of lactose particles. Typicalexamples of commercially available sieving apparatus are made availableby Russell Finex of Charlotte, N.C. and Alpine Sieves of Augsburg,Germany.

In another embodiment, the plurality of lactose particles containing nomore than 10% w/w of lactose particles having a volume average particlesize of about 70 microns or less may be obtained by classifying a sourceof lactose into two fractions comprising the plurality of lactoseparticles containing no more than 10% w/w of lactose particles having avolume average particle size of about 70 microns or less and a remainingfine fraction. One example of a commercially preferred classifier madecommercially available by Hosakawa of Cheshire, United Kingdom. Theremaining fine fraction of lactose is lactose that is unmilled orcrystalline. Optionally, prior to classifying, the particles may besubjected to sieving.

FIG. 5 illustrates the full particle size profile of the initial feedbatches before the smaller crystals have been removed by classification.FIG. 6 illustrates the full particle size profile after the smallercrystals have been removed via a classification process. This results ina much more uniform feed material being presented to the mill.

The Span is often a parameter used to describe the narrowness/broadnessof a distribution of particles. The Span is given by the followingformulation:

(D90−D10)/D50=Span

The term “D90” is defined as the size in microns below which 90 percentof the particles reside on a volume basis.

The term “D10” is defined as the size in microns below which 10 percentof the particles reside on a volume basis.

Although not intending to be bound by theory, for particles with similarD50's the smaller the Span, the tighter are the distribution ofparticles. In general, feed lactose batches with small Span values wouldbe better input materials to the mill as this would indicate a narrowerparticle size distribution. It can be seen from FIG. 7 that the higherthe D10 values are for typical crystalline A Feed lactose batches, thesmaller the Span values. The following Tables 1-2 illustrate thattighter particle size distributions are obtained after theclassification of the crystalline A Feed lactose, and hence produce apreferred input into the mill

TABLE 1 Malvern Data Prior to classification D10 D50 D90 Span Example 1Fine feed 57 123 208 1.23 Example 1 coarse feed 86 176 284 1.13 Example2 Fine feed 53 114 208 1.36 Example 2 coarse feed 84 162 270 1.15Example 3 Fine feed 53 114 207 1.35 Example 3 coarse feed 81 161 2741.20

TABLE 2 Malvern Data after classification D10 D50 D90 Span Example 1Fine feed 88 141 219 0.93 Example 1 coarse feed 116 186 284 0.90 Example2 Fine feed 79 140 236 1.12 Example 2 coarse feed 107 171 263 0.91Example 3 Fine feed 81 139 230 1.07 Example 3 coarse feed 104 171 2700.97

The step of milling the plurality of lactose particles to yield aplurality of milled lactose particles may be carried out using knowntechniques. As an example, in one embodiment, milling may be performedusing an impact mill (e.g., air classifier mill, (ACM)) whereby sizereduction of pharmaceutical grade lactose is a combination of millingand classification. In one embodiment, milling is conducted using astandard air classifier mill fitted with mill rotor and grinding pins,classifier wheel and grinding track. One example of a commerciallypreferred mill is the MikroPul ACM made commercially available byHosakawa.

The process described herein is suitable for providing lactose for usein a wide range of inhalation applications, encompassing those thatrequire very fine lactose to those requiring much coarser lactose. Suchthat in one embodiment the coarse fraction alone may be suitable forpharmaceutical applications and at the other extreme the fine fractionalone may be suitable for pharmaceutical applications. Required FPMassperformance from inhalation devices, including, in one embodiment andwithout limitation Advair, can be targeted by the combination ofappropriate amounts of the coarse and fine fractions. This can cover thecomplete range from 100 percent coarse fraction +0 percent fine fractionto 100 percent fine fraction +0 percent coarse fraction. The exactproportions that are required will depend on the particle size profileof each of the coarse and fine fractions themselves.

As an example, the above combining step may be achieved by blending,although other procedures may be employed. A typical blender used wouldbe of the orbital screw type such as the Vrieco-Nauta Conical Blendermade commercially available by Hosakawa.

In another aspect, the invention may encompass pharmaceuticalformulations formed according to various processes set forth herein.

Medicaments, for the purposes of the invention, include a variety ofpharmaceutically active ingredients, such as, for example, those whichare useful in inhalation therapy. In general, the term “medicament” isto be broadly construed and include, without limitation, actives, drugsand bioactive agents, as well as biopharmaceuticals. Various embodimentsmay include medicament present in micronized form. Appropriatemedicaments may thus be selected from, for example, analgesics, (e.g.,codeine, dihydromorphine, ergotamine, fentanyl or morphine); anginalpreparations, (e.g., diltiazem); antiallergics, e.g., cromoglicate,ketotifen or nedocromil); antiinfectives (e.g., cephalosporins,penicillins, streptomycin, sulphonamides, tetracyclines andpentamidine); antihistamines, (e.g., methapyrilene);anti-inflammatories, (e.g., beclometasone dipropionate, fluticasonepropionate, flunisolide, budesonide, rofleponide, mometasone furoate,ciclesonide, triamcinolone acetonide, 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester), (6α, 11β, 16α,17β)-6,9-difluoro-17-{[(fluoromethyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl2-furoate, and (6α, 11β, 16α,17α)-6,9-difluoro-17-{[(fluoromethyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl4-methyl-1,3-thiazole-5-carboxylate); antitussives, (e.g., noscapine);bronchodilators, e.g., albuterol (e.g. as sulphate), salmeterol (e.g. asxinafoate), ephedrine, adrenaline, fenoterol (e.g as hydrobromide),formoterol (e.g., as fumarate), isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol (e.g., as acetate),reproterol (e.g., as hydrochloride), rimiterol, terbutaline (e.g., assulphate), isoetharine,tulobuterol,4-hydroxy-7-[2-[2-[[3-(2-(henylethoxy)propyl]sulfonyl]ethyl]-amino]ethyl-2(3H)-benzothiazolone),3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide,3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide,4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol,2-hydroxy-5-((1R)-1-hydroxy-2-{[2-(4-{[(2R)-2-hydroxy-2-phenylethyl]amino}phenyl)ethyl]amino}ethyl)phenylformamide,8-hydroxy-5-{(1R)-1-hydroxy-2-[(2-{4-[(6-methoxy-1,1′-biphenyl-3-yl)amino]phenyl}ethyl)amino]ethyl}quinolin-2(1H)-one,5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one;diuretics, (e.g., amiloride,; anticholinergics, e.g., ipratropium (e.g.,as bromide), tiotropium, atropine or oxitropium); hormones, (e.g.,cortisone, hydrocortisone or prednisolone); xanthines, (e.g.,aminophylline, choline theophyllinate, lysine theophyllinate ortheophylline); therapeutic proteins and peptides, (e.g., insulin). Itwill be clear to a person skilled in the art that, where appropriate,the medicaments may be used in the form of salts, (e.g., as alkali metalor amine salts or as acid addition salts) or as esters (e.g., loweralkyl esters) or as solvates (e.g., hydrates) to optimise the activityand/or stability of the medicament. It will be further clear to a personskilled in the art that where appropriate, the medicaments may be usedin the form of a pure isomer, for example, R-salbutamol orRR-formoterol.

Particular medicaments for administration using pharmaceuticalformulations in accordance with the invention include anti-allergics,bronchodilators, beta agonists (e.g., long-acting beta agonists), andanti-inflammatory steroids of use in the treatment of respiratoryconditions as defined herein by inhalation therapy, for examplecromoglicate (e.g. as the sodium salt), salbutamol (e.g. as the freebase or the sulphate salt), salmeterol (e.g. as the xinafoate salt),bitolterol, formoterol (e.g. as the fumarate salt), terbutaline (e.g. asthe sulphate salt), reproterol (e.g. as the hydrochloride salt), abeclometasone ester (e.g. the dipropionate), a fluticasone ester (e.g.the propionate), a mometasone ester (e.g., the furoate), budesonide,dexamethasone, flunisolide, triamcinolone, tripredane,(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione. Medicaments useful inerectile dysfunction treatment (e.g., PDE-V inhibitors such asvardenafil hydrochloride, along with alprostadil and sildenafil citrate)may also be employed. It should be understood that the medicaments thatmay be used in conjunction with the inhaler are not limited to thosedescribed herein.

Salmeterol, especially salmeterol xinafoate, salbutamol, fluticasonepropionate, beclomethasone dipropionate and physiologically acceptablesalts and solvates thereof may be employed.

It will be appreciated by those skilled in the art that the formulationsaccording to the invention may, if desired, contain a combination of twoor more medicaments. Formulations containing two active ingredients areknown for the treatment and/or prophylaxis of respiratory disorders suchas asthma and COPD, and may include, for example, formoterol (e.g. asthe fumarate) and budesonide, salmeterol (e.g. as the xinafoate salt)and fluticasone (e.g. as the propionate ester), salbutamol (e.g. as freebase or sulphate salt) and beclometasone (as the dipropionate ester).

In one embodiment, a particular combination that may be employed is acombination of a beta agonist (e.g., a long-acting beta agonist) and ananti-inflammatory steroid. One embodiment encompasses a combination offluticasone propionate and salmeterol, or a salt thereof (particularlythe xinafoate salt). The ratio of salmeterol to fluticasone propionatein the formulations according to the present invention is preferablywithin the range 4:1 to 1:20. The two drugs may be administered invarious manners, simultaneously, sequentially, or separately, in thesame or different ratios. In various embodiments, each metered dose oractuation of the inhaler will typically contain from 25 μg to 100 μg ofsalmeterol and from 25 μg to 500 μg of fluticasone propionate. Thepharmaceutical formulation may be administered as a formulationaccording to various occurrences per day. In one embodiment, thepharmaceutical formulation is administered twice daily.

Embodiments of specific medicament combinations that may be used invarious pharmaceutical formulations are as follows:

1) fluticasone propionate 100 μg/salmeterol xinafoate 72.5 μg(equivalent to salmeterol base 50 μg)

2) fluticasone propionate 250 μg/salmeterol xinafoate 72.5 μg(equivalent to salmeterol base 50 μg)

3) fluticasone propionate 500 μg/salmeterol xinafoate 72.5 μg(equivalent to salmeterol base 50 μg)

In various embodiments, the pharmaceutical formulations may be presentin the form of various inhalable formulations. In one embodiment, thepharmaceutical formulation is present in the form of a dry powderformulation, the formulation of such may be carried out according toknown techniques. The invention also encompasses inhalation devicesincluding inhalable formulations. Dry powder formulations for topicaldelivery to the lung by inhalation may, for example, be presented incapsules and cartridges of for example gelatine, or blisters of forexample laminated aluminum foil, for use in an inhaler or insufflator.Powder blend formulations generally contain a powder mix for inhalationof the compound of the invention and a suitable powder base whichincludes lactose and, optionally, at least one additional excipient(e.g., carrier, diluent, etc.). In various embodiments, each capsule orcartridge may generally contain between 20 μg and 10 mg of the at leastone medicament. In one embodiment, the formulation may be formed intoparticles comprising at least one medicament, and excipient material(s),such as by co-precipitation or coating. When employed as a dry powder,packaging of the formulation may be suitable for unit dose or multi-dosedelivery. In the case of multi-dose delivery, the formulation can bepre-metered (e.g., as in Diskus®, see GB 2242134/U.S. Pat. Nos.6,032,666, 5,860,419, 5,873,360, 5,590,645, 6,378,519 and 6,536,427 orDiskhaler, see GB 2178965, 2129691 and 2169265, U.S. Pat. Nos.4,778,054, 4,811,731, 5,035,237) or metered in use (e.g. as inTurbuhaler, see EP 69715, or in the devices described in U.S. Pat. No.6,321,747). An example of a unit-dose device is Rotahaler (see GB2064336). In one embodiment, the Diskus® inhalation device comprises anelongate strip formed from a base sheet having a plurality of recessesspaced along its length and a lid sheet hermetically but peelably sealedthereto to define a plurality of containers, each container havingtherein an inhalable formulation containing the at least one medicament,the lactose, optionally with other excipients. Preferably, the strip issufficiently flexible to be wound into a roll. The lid sheet and basesheet will preferably have leading end portions which are not sealed toone another and at least one of the leading end portions is constructedto be attached to a winding means. Also, preferably the hermetic sealbetween the base and lid sheets extends over their whole width. The lidsheet may preferably be peeled from the base sheet in a longitudinaldirection from a first end of the base sheet.

In one embodiment, the formulations may be employed in or as suspensionsor as aerosols delivered from pressurised packs, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,2-tetrafluoroethane, carbondioxide or other suitable gas. Such formulations may be delivered via apressurized inhaler, e.g., a Metered Dose Inhaler (MDI). Exemplary MDIstypically include canisters suitable for delivering the pharmaceuticalformulations. Canisters generally comprise a container capable ofwithstanding the vapour pressure of the propellant used such as aplastic or plastic-coated glass bottle or preferably a metal can, forexample an aluminum can which may optionally be anodised, lacquer-coatedand/or plastic-coated, which container is closed with a metering valve.Aluminum cans which have their inner surfaces coated with a fluorocarbonpolymer are particularly preferred. Such polymers can be made ofmultiples of the following monomeric units: tetrafluoroethylene (PTFE),fluorinated ethylene propylene (FEP), perfluoroalkoxyalkane (PFA),ethylene tetrafluoroethylene (EFTE), vinyldienefluoride (PVDF), andchlorinated ethylene tetrafluoroethylene. Embodiments of coatings usedon all or part of the internal surfaces of an MDI are set forth in U.S.Pat. Nos. 6,143,277; 6,511,653; 6,253,762; 6,532,955; and 6,546,928.

MDIs may also include metering valves are designed to deliver a meteredamount of the formulation per actuation and incorporate a gasket toprevent leakage of propellant through the valve. The gasket may compriseany suitable elastomeric material such as for example low densitypolyethylene, chlorobutyl, black and white butadiene-acrylonitrilerubbers, butyl rubber and neoprene. Suitable valves are commerciallyavailable from manufacturers well known in the aerosol industry, forexample, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK(e.g. BK300, BK356) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser™).Embodiments of metering valves are set forth in U.S. Pat. Nos.6,170,717; 6,315,173; and 6,318,603.

In various embodiments, the MDIs may also be used in conjunction withother structures such as, without limitation, overwrap packages forstoring and containing the MDIs, including those described in U.S. Pat.No. 6,390,291, as well as dose counter units such as, but not limitedto, those described in U.S. Pat. Nos. 6,360,739 and 6,431,168.

In addition to the above, the pharmaceutical formulations can beemployed in capsules, sachets, tablet buccals, lozenges, papers, orother container. Moreover, the formulations can be in the form oftablets, pills, powders, elixirs, suspensions, emulsions, solutions,syrups, capsules (such as, for example, soft and hard gelatin capsules),suppositories, sterile injectable solutions, and sterile packagedpowders. Excipients, carriers, diluents, and the like may be optionallyemployed.

The pharmaceutical formulation formed by the processes of the inventionmay be used in the treatment of a number of respiratory disorders, whichencompasses, for example, maintenance treatment and/or prophylaxis. Suchrespiratory conditions include, without limitation, diseases andconditions associated with reversible airways obstruction such asasthma, chronic obstructive pulmonary diseases (COPD) (e.g. chronic andwheezy bronchitis, emphysema), respiratory tract infection and upperrespiratory tract disease (e.g. rhinitis, such as allergic and seasonalrhinitis). Such treatment is carried out by delivering medicament to amammal. Accordingly, and in view of the above, in another aspect, theinvention provides a method for the treatment of a respiratory disordercomprising the step of administering a pharmaceutically effective amountof a pharmaceutical formulation to a mammal such as, for example, ahuman. For the purposes of the invention, the term “pharmaceuticallyeffective amount” is to be broadly interpreted and encompass thetreatment of the disorder. In one embodiment, the administration iscarried out via an inhalation device described herein. In oneembodiment, the administration is carried out by nasal or oralinhalation.

The invention offers potential advantages relative to the prior art. Asone example, the invention allows for improved control of particle sizedistribution of the lactose formed by this process, i.e., a moreconsistent particle size distribution and/or a more consistent surfacemorphology of the lactose is capable of being achieved from lactosefeeds independent of the particle size distribution of the lactose feed.In particular, the lactose formed by the process of the invention iscapable of exhibiting a more continuous particle size distribution,i.e., very little or no gap in the particle size distribution incontrast to the distribution set forth in X. M. Zeng et al.,International Journal of Pharmaceutics, 176 (1998) 99-110.

The present invention is highly advantageous. In one embodiment, forexample, the classification cut-point can be chosen so that the coarsefraction is suitable for use in a pharmaceutical formulation withoutfine fraction. In one embodiment, at least a portion of the finefraction (ranging from 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45 to 55,60, 65, 70, 75, 80, 85, 90, 95 or 100 percent by weight) may be combined(e.g., blended) with at least a portion of the coarse fraction (rangingfrom 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45 to 55, 60, 65, 70, 75, 80,85, 90, 95 or 100 percent by weight) such that the resulting lactosecomposition is suitable for use in a pharmaceutical formulation. In oneembodiment, the fine fraction may be used in a pharmaceuticalformulation without any coarse fraction. With respect to the aboveembodiments, it is preferred that lactose be employed with sufficientfine material so as to be capable of meeting the FPMass requirements,typically 20 percent to 30 percent (weight basis) of the medicamentcontent achieved by utilising lactose that comprises 2 percent to 10percent (volume basis) particles less than 4.5 microns as measured bySympatec.

In view of the above, in one embodiment, the invention may furthercomprise combining at least one medicament with a lactose composition toform a pharmaceutical formulation. The lactose composition in such anembodiment may comprise from 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45 to55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 percent by weight of thecoarse fraction and from 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45 to 55,60, 65, 70, 75, 80, 85, 90, 95 or 100 percent by weight of the finefraction. Moreover, in one embodiment, the invention may furthercomprise combining at least a portion of the coarse fraction with atleast a portion of the fine fraction to form a lactose composition; andthereafter combining the lactose composition with at least onemedicament to form a pharmaceutical formulation. Alternatively, in oneembodiment, the invention may encompass simultaneously combining: (i)from 0, 5, 10, 15, 20, 25, 30, 35, 40, or 45 to 55, 60, 65, 70, 75, 80,85, 90, 95 or 100 percent by weight of coarse fraction, (ii) from 0, 5,10, 15, 20, 25, 30, 35, 40, or 45 to 55, 60, 65, 70, 75, 80, 85, 90, 95or 100 percent by weight of fine fraction, and (iii) at least onemedicament to form a pharmaceutical formulation.

As the large majority of the small particles have been produced bymilling, they all typically possess a similar surface roughness. Bycomparison, if lactose batches are introduced into the mill that containparticles less than a volume average size of 70 microns, then theseparticles will essentially pass through the mill without the need to bereduced in size by the milling action. As a consequence, these particleswill still exhibit a smoother crystalline surface, compared to milledlactose particles, which in turn may lead to different interactions withthe active molecules.

Thus by substantially reducing or eliminating these small crystallineparticles from the feed to the mill, not only can the milled particlesize be controlled, but the particles will also exhibit a very much moreuniform surface morphology.

Malvern Methodology

Malvern measurements as set forth herein are determined according to thefollowing:

Equipment

-   -   Malvern Mastersizer, laser diffraction particle size analyser        fitted with the 300 mm focal length lens.    -   MS15 stainless steel flow-through measurement cell, 2.2 mm path        width (Malvern).    -   MSX1 small volume presentation unit (Malvern).    -   Viton tubing: 4.8 mm internal diameter, 1.6 mm wall thickness        (Watson-Marlow).    -   Viton or Neoprene tubing: approximately 15 mm internal diameter,        2 mm wall thickness (Watson-Marlow).    -   Positive pressure or vacuum filtration equipment with 0.22 μm        maximum aperture membrane filters type GV (Sartorius/Millipore).    -   Analytical balance (Mettler, electronic) minimum weighing        capacity of 30 grams with an accuracy to 4 decimal places,        Spatulas for sample transfer.

Solvent: HPLC grade iso-octane

Test Method

This section outlines the procedure for the measurement of one batch oflactose. For each batch, it is preferred that three representativesamples be measured in duplicate.

Preparation of the Liquid Dispersant.

-   -   For the preparation of 2 litres of liquid dispersant, dissolve        with ultrasonication 0.7 g of lecithin NF in 10 cm³ of        iso-octane to produce a dispersant concentrate.    -   Filter sufficient iso-octane using the vacuum filtration unit        and a 0.22 μm filter disc. During this filtration add the        dispersant concentrate to the solvent so that it too is filtered        and mixed in. Store in a pre-cleaned Winchester solvent        container (Liquid dispersant).    -   The filtered liquid dispersant should be stored in a solvent        cupboard when not in use.    -   Liquid dispersant may be recycled by refiltering after analysis        as from above and making up to volume with iso-octane

Preparation of the Malvern Mastersizer

-   -   Set up the following measurement parameters on the Malvern        Mastersizer for the test sample:

Model type: Model independent Presentation code: 0503 Focal length: 300mm Beam active length:  2.2 mm Gain: Low Trigger: Internal Kill datalow: 0 Kill data high: 0 Shape correction: Off Density: 1.00 Autorunnumber: 0 Obscuration range: Between 0.18 and 0.22 Sweeps for measure:1000 Sweeps for inspect: 50

-   -   Set up the MSX1 small volume presentation unit ensuring that the        total length Viton tubing from the presentation unit to the flow        through cell does not exceed 30 cm. Attach one end of suitably        sized (int. dia. approx. 15 mm) Viton or Neoprene tubing (waste        tubing) to the waste drain and place the other end into a red        non-chlorinated waste solvent container placed on the floor.    -   Flush the presentation unit and the cell through with the liquid        dispersant and drain.    -   Refill with the iso-octane/lecithin dispersant and align the        laser beam using a stirrer speed of 11 o'clock (1500±100 rpm).        The laser intensity should be in the “good” region.    -   Once the laser is aligned, it is preferred that the stirrer        speed should not be altered.

Sample Measurement

-   -   Add the powder sample to a presentation unit using a spatula to        obtain an obscuration value within the range 0.18 to 0.22.    -   Allow 60 seconds to allow the dispersion to equilibrate and the        obscuration value to stabilise.    -   Measure the particle size distribution. Repeat measurement as        deemed appropriate.

Sympatec Methodology

The following teachings may be employed to arrive at the Sympatecmeasurements described herein:

Instrumental Parameters

Parameter Typical Measuring Range R5: 0.5/4.5→875 μm Trigger Conditions10 s, 100 ms, 0.2% ch12 Time Base 100 ms Reference measurement 10 s,Single Focus Prior to first measurement No Start 0 s after channel 12 ≧0.2% Valid Always Stop 5 s after channel 12 ≦ 0.2% Or After 30 s realtime Dispersing Device RODOS VIBRI Chute Standard chute Gap Width 2 mmPressure Nominal 1.5 Bar (1.3-1.7 Bar acceptable) Depression Maximise(see LSOP/WARE/092/03 section 5.2.9). Feed Rate 85% Sample Weight 2 g ±1 g

The Sympatec HELOS is provided with the RODOS dry powder dispersion unitand the VIBRI vibratory feeder.

In these measurements, software is used in conjunction with themeasurement equipment.

For the RODOS dispersing system, the primary pressure of the injectorshould be adjusted using the pressure control dial. The primary pressureshould be within the range 1.3-1.7 bar although a pressure of 1.5 barshould be aimed for at each run. The injector depression should beoptimised using the adjustment ring. The direction in which the adjusterring is turned (clockwise or anti clockwise), has no adverse effect onthe depression obtained. On instruments with a RODOS/M dispersingsystem, the primary pressure may be adjusted using a software algorithm.The injector depression should be maximised by clicking the “Auto-adjustdepr” button. The instrument should not be used if the injectordepression is less than 55 mbar at 1.3-1.7 bar.

Analysis of Sample

Homogenize the sample by turning the pot slowly end-over-end at leastten times in one direction and ten times in the other direction prior toanalysis. This is only necessary the first time a sample is taken from apot.

Transfer 2±1 g of the lactose sample into the funnel attached to theVIBRI using a Kartell “spoon/flat” general purpose spatula (Fishercatalogue no SMJ-410-091M, volume approximately 1.8 cm³).

A heaped spoonful of lactose powder has been demonstrated to present asample in the range 2.0-3.0 g.

The invention will now be described with respect to the followingexamples. It should be appreciated that the examples are set forth forillustrative purposes only, and do not limit the scope of the inventionas defined by the claims.

EXAMPLE 1 Lactose Processing

Two batches of coarse crystalline lactose A were selected. Thesediffered from each other inasmuch that they exhibited different D50's.Batch 1 had a D50 of between 110-130 microns and Batch 2 had a D50 ofbetween 160-180 microns, as measured by Malvern laser particle sizingtechniques.

Each of these batches were then separated into a fine and coarsefraction using an air classifier. The cut point was nominally about 80microns.

In each case the fine fraction was discarded and the coarse fractionswere milled in an air classifier mill (ACM) so that the D50 of themilled product was nominally 60-70 microns.

The milled lactose batches were then classified at a cut point ofnominally 25 microns to form a fine fraction and a coarse fraction.

Suitable proportions of the coarse and fine fraction from each milledbatch were blended together so that the percentage of lactose <4.5microns was:

(i) 6.7%+/−0.3%; ex batch 1(ii) 5.0%+/−0.3%; ex batch 11(iii) 3.3%+/−0.3%; ex batch 1(iv) 6.7%+1-0.3%; ex batch 2(v) 5.0%+/−0.3%; ex batch 2(vi) 3.3%+/−0.3%; ex batch 2

The above teachings are exemplified by the following protocol:

The purpose of the following development protocol is to manufacturelactose batches having the same overall particle size distribution fromdifferent feed crystalline lactose A batches.

The feed, milling, classifying, and blending of lactose may be carriedout using the following:

-   -   1) A pilot scale blender capable of blending 100 kg of material        (“pilot scale blender”)    -   2) A full scale classifier, e.g., a classifier that may be        employed as a stand alone device suitable for full scale        production (“full scale classifier”)

The following experimental method may be employed:

1. Select 2 batches of crystalline lactose A that are different fromeach other in their percentage of lactose that is less than 80 microns.Crystalline Lactose A is employed as feed lactose and is madecommercially available by Borculo Domo Ingredients of Borculo,Netherlands.

These are defined as batch 1, which has a D50 of between 120-130 micronsand batch 2 that has a D50 of 170-180 microns. Batch 1 should have thepercentage less than 15 microns greater than 3%, whereas batch 2 shouldhave the percentage of lactose less than 15 microns as less than 1.5%.

2. Using the full scale classifier, separate each full batch as cleanlyas possible into two fractions, one being <80 microns and the otherbeing >80 microns. The same settings should be used for both batches andit is desirable that no changes are to be made to the settings duringthe classification.

3. Mill only the fraction of lactose that is >80 microns from bothbatches 1 and 2. Set the mill at nominally the same as used forcommercial supply however, reduce the throughput rate of the lactose sothat the milling and built in classifier can act more efficiently. Onceset, discard any test millings and then mill each batch of lactose >80microns at the same settings.

4. Using the full scale classifier, separate each milled batch ascleanly as possible into two fractions, one being nominally <25 micronsand the other being nominally >25 microns. The same settings should beused for both batches and it is desirable no changes are to be made tothe settings during the classification.

5. Recombination by blending: Using appropriate aliquots from each batchof the classified fractions, recombine the lactose in the pilot scaleblender to give:

a—100 kgs of product which has the percentage of lactose <4.5 microns at6.7%+/−0.3%—From feed batch 1

b—100 kgs of product which has the percentage of lactose <4.5 microns at5.0%+/−0.3%—From feed batch 1

c—100 kgs of product which has the percentage of lactose <4.5 microns at3.3%+/−0.3%—From feed batch 1

This may be repeated using lactose from the second feed batch. (d)should be as similar to (a) as possible.

d—100 kgs of product which has the percentage of lactose <4.5 microns at6.7%+/−0.3%—From feed batch 2

e—100 kgs of product which has the percentage of lactose <4.5 microns at5.0%+/−0.3%—From feed batch 2

f—100 kgs of product which has the percentage of lactose <4.5 microns at3.3%+/−0.3%—From feed batch 2

6. Dispense lactose from blender into 20 kg tie sealed polyethylenebags, heat sealed in a foil laminate bag and pack inside a cardboardbox. Pack at least 5 boxes from each batch.

EXAMPLE 2 Lactose Processing

Two batches of coarse crystalline lactose A were selected. Thesediffered from each other inasmuch that they exhibited different D50's.Batch 1 had a D50 of between 110-130 microns and Batch 2 had a D50 ofbetween 160-180 microns, as measured by Malvern laser particle sizingtechniques.

Each of these batches were then separated into a fine and coarsefraction using an air classifier. The cut point was nominally about 80microns.

In each case the fine fraction was discarded and the coarse fractionswere milled in an air classifier mill (ACM) so that the D50 of themilled product was nominally 60-70 microns.

Both milled lactose batches were then put through a 150 micron sieve.This is an additional step compared to Example 1.

The milled lactose batches were then classified at a cut point ofnominally 25 microns to form a fine fraction and a coarse fraction.

Suitable proportions of the coarse and fine fraction from each milledbatch were blended together so that the percentage of lactose <4.5microns was:

(i) 6.7%+/−0.3%; ex batch 1(ii) 5.0%+/−0.3%; ex batch 1(iii) 3.3%+/−0.3%; ex batch 1(i) 6.7%+1-0.3%; ex batch 2(ii) 5.0%+/−0.3%; ex batch 2(iii) 3.3%+/−0.3%; ex batch 2

The unit operation of this protocol pertains to the process ofclassification of feed, milling, classifying, sieving, and blending oflactose.

The following equipment may be used:

pilot scale blender

full scale classifier

The purpose of this example is to manufacture lactose batches with thesame overall particle size distribution from different feed batches.This work will use the Full Scale Classifier.

The above teachings are exemplified by the following protocol:

1. Select two batches of crystalline lactose A, batch 1 that has a D50of 120-130 microns, and the percentage lactose less than 15 microns isgreater than 3%, and batch 2 with an D50 of 170-180 microns and thepercentage lactose less than 15 microns is less than 1.5%. For thepurposes of this protocol however, the D50 range was altered such thatthe batch 1 D50 was from 110-130 microns and the batch 2 D50 was from160-180 microns.

Treat each of these big bags in an identical fashion as described instages 2 through to 5.

2. Using the full scale classifier, separate the whole batch as cleanlyas possible into two fractions, one being <80 microns and the otherbeing >80 microns. The same settings should be used as those used inExample 1 and it is desirable that no changes be made to the settingsduring the classification.

3. Mill the coarse fraction obtained from 2. Set the mill at nominallythe same as used for typical lactose milling. Once the mill is set,discard any test millings and then mill the coarse fractions from thebatch at the same settings.

4. Sieve the milled material through a 150-micron sieve.

5. Using the full scale classifier, separate each sieved milled batch ascleanly as possible into two fractions, one being nominally <25 micronsand the other being nominally >25 microns. These settings should remainconstant during the classification of the batch.

6. Recombination by blending: Using appropriate coarse and fine aliquotsfrom batches 1 and 2 at the end of stage 5, recombine the lactose in thepilot scale blender to give:

a—100 kgs of product which has the percentage of lactose <4.5 microns at6.7%+/−0.3%—(batch 1, Fine Feed)

b—100 kgs of product which has the percentage of lactose <4.5 microns at6.7%+/−0.3%—(batch 2, Coarse Feed)

No Targets for the D50 are given for these recombinations, 60-90 micronswould be ideal.

7. Dispense lactose from blender into 20 kg tie sealed polythene bags,heat sealed in a foil laminate bag and pack inside a cardboard box. Packat least 5 boxes from each batch.

EXAMPLE 3 Lactose Processing

Two batches of coarse crystalline lactose A were selected. Thesediffered from each other inasmuch that they exhibited different D50's.Batch 1 had a D50 of between 110-130 microns and Batch 2 had a D50 ofbetween 160-180 microns, as measured by Malvern laser particle sizingtechniques.

Each of these batches were then separated into a fine and coarsefraction using an air classifier. The cut point was nominally about 80microns.

In each case the fine fraction was discarded and the coarse fractionswere milled in an air classifier mill (ACM) so that the D50 of themilled product was nominally 60-70 microns.

The milled lactose batches were then classified at a cut point ofnominally 25 microns to form a fine fraction and a coarse fraction.

Suitable proportions of the coarse and fine fraction from each milledbatch were blended together so that the percentage of lactose <4.5microns was:

(i) 6.3%+1-0.3%; ex batch 1(ii) 6.0%+/−0.3%; ex batch 1(iii) 5.5%+/−0.3%; ex batch 1(i) 6.3%+/−0.3%; ex batch 2(ii) 6.0%+/−0.3%; ex batch 2(iii) 5.5%+/−0.3%; ex batch 2

The above teachings are exemplified by the following protocol:

The unit operation of this protocol pertains to the process ofclassification of feed, milling, classifying, sieving, and blending oflactose.

The purpose of the protocol set forth in this example is to manufacturelactose batches with the same overall particle size distribution fromdifferent feed batches. This work will use the full scale classifier.

The protocol is as follows:

1. Select two batches of crystalline lactose A, batch 1 that has a D50of 120-130 microns, and the percentage lactose less than 15 microns isgreater than 3%, and batch 2 with an D50 of 170-180 microns and thepercentage lactose less than 15 microns is less than 1.5%. For thepurposes of this protocol however, the D50 range was altered such thatthe batch 1 D50 was from 110-130 microns and the batch 2 D50 was from160-180 microns.

Treat each of these big bags in an identical fashion as described instages 2 through to 4.

2. Using the full scale classifier, separate the whole batch as cleanlyas possible into two fractions, one being <80 microns and the otherbeing >80 microns. The same settings should be used as those used inExample 2, these are shown in Table 3 below. It is preferable that nochanges are to be made to the settings during the classification.

TABLE 3 Settings Readings Calculated Classifierspeed 4.1 Hz 246 rpmFeedrate 15 Hz 12 Rpm 250 Kg/hour Transport air 1500 Rpm 25 Hz min 135m3/h max 165 m3/h Washair 1500 Rpm 25 Hz min 390 m3/h max 450 m3/h

3. Using the full scale classifier with the settings in Table 4,separate each milled batch as cleanly as possible into two fractions,one being nominally <25 microns and the other being nominally >25microns.

TABLE 4 Settings Readings Calculated Classifierspeed 10 Hz 600 rpmFeedrate 25 Hz 20 Rpm 410 KG/hour Transport air min 175 m3/h max 235m3/h Washair min 620 m3/h max 675 m3/h Airsystem 2100 Rpm 35 Hz

The above settings are capable of providing batches that areapproximately 80% wt/wt coarse material and 20% wt/wt fine material.

4. Recombination by blending: Using appropriate coarse and fine aliquotsfrom batches 1 and 2 at the end of stage 3, recombine the lactose in thepilot scale blender to give:

a—100 kgs of product which has the percentage of lactose <4.5 microns at6.3%+/−0.3%—From feed batch 1

b—100 kgs of product which has the percentage of lactose <4.5 microns at6.0%+1-0.3%—From feed batch 1

c—100 kgs of product which has the percentage of lactose <4.5 microns at5.5%+/−0.3%—From feed batch 1

This to be repeated using lactose from the second feed batch.

d—100 kgs of product which has the percentage of lactose <4.5 microns at6.3%+/−0.3%—From feed batch 2

e—100 kgs of product which has the percentage of lactose <4.5 microns at6.0%+/−0.3%—From feed batch 2

f—100 kgs of product which has the percentage of lactose <4.5 microns at5.5%+/−0.3%—From feed batch 2

-   -   Use the same amounts of fines and coarse in each pair of the        combinations.    -   Ensure data on Malvern and Sympatec sheets agree with data in        the table.

TABLE 5 Particle Size Data for Typical Lactose Production Coarsefraction Fine fraction D90 % 15 μm Batch number D10 fine D50 fine D90fine 15 μm fine D10 Coarse D50 Coarse Coarse coarse Normal ProductionData 1 7.9 23 53 30.5 29 84 183 4.5 2 6.9 19 43 38.9 29 79 169 4.7 3 6.620 51 38.5 27 81 161 5.8 4 7.6 20 53 36.4 25 77 151 5.6 5 6.6 18 44 42.731 82 160 6.5 6 7.7 24 51 29.9 46 92 168 1 7 7.9 21 48 32.5 45 92 169 18 8.2 24 52 28 40 79 143 1.5 9 8.3 25 57 27.3 46 93 167 1.3 10 7.2 20 4834.7 34 84 138 2.5 11 7.3 20 47 35.1 46 97 184 1 12 7 18 34 39.6 46 104205 1 13 7.4 19 42 36.9 48 101 184 0.9 14 7.7 19 40 36.5 47 101 191 0.715 7.7 19 40 36.5 46 102 200 0.8 16 7.8 21 47 32.2 46 94 175 0.8 17 7.522 56 32.2 47 94 171 0.5 18 7.5 22 56 32.2 48 94 171 0.5 19 6.5 20 45 3529 88 184 4.6 20 6.5 20 45 38.1 52 102 185 0.6 21 6.5 20 46 38.5 48 97188 1 22 6.5 19 42 38.7 47 105 202 1.2 23 7.3 21 45 33.7 50 100 180 0.924 7.1 20 44 34.9 46 92 169 1.3 25 6.9 20 43 37.4 48 95 170 0.9 26 5.821 49 36.9 39 83 158 2.4 27 5.9 21 51 36.4 40 82 157 2.2 28 5.7 20 4538.9 43 91 174 1.97 29 6.9 23 54 32 34 92 185 3.2 30 6.9 23 54 32.3 3391 184 3.8 31 6.1 22 50 35.19 51 99 181 0.75 32 6.4 22 49 34.7 50 97 1800.9 33 6.9 24 58 31.37 50 95 176 0.91 34 6.9 18 36 40 46 100 198 0.2 356.5 18 40 40 42 84 158 1.1 36 6.3 18 44 40 40 81 154 1.5 37 6.8 19 43 3943 84 158 1.1 38 6 18 42 42 40 81 155 1.4 39 6 18 41 42 42 88 168 1.5 407 19 43 38 44 93 182 0.8 41 6.7 19 42 39 44 94 184 0.8 42 6.2 18 40 4342 90 180 1 43 6 17 40 43 41 85 168 1.3 44 6.4 18 40 41 42 85 165 1 456.9 17 37 42 40 82 161 1 46 6.9 18 40 41 40 82 162 0.9 47 6.6 17 40 4238 87 177 1.2 48 6.8 18 45 40 38 85 173 1.2 49 6.4 17 37 45 41 86 1701.2 50 6.1 15 33 48 41 92 187 1 51 6.6 17 37 44 41 87 167 1 52 5.8 15 3352 33 86 170 2.3 53 6 14 32 52.3 34 85 167 2 54 6.8 16 38 45.8 38 92 1731.4 55 6.6 14 26 57 34 80 156 2.3 56 6.8 15 29 51 30 74 147 2.8 57 6.315 31 51 39 90 170 1.6 58 6.6 18 53 43.6 40 91 174 1.7 59 7.5 20 44 35.240 88 168 2.4 60 7.8 23 51 30.3 45 92 166 1.7 61 7.5 22 48 33 43 87 1581.8 62 7.4 22 50 32.5 44 89 164 1.5 63 7.6 22 49 32.6 47 97 184 1.4 647.7 24 53 29.6 47 96 186 1.1 65 7.5 23 52 31.3 45 93 181 1.2 66 7 21 4934.8 46 94 179 1.3 67 6.8 20 48 36.2 46 96 178 1.5 68 7.3 20 44 35.8 4898 178 1.3 69 7.1 19 44 37.2 48 97 172 1.6 70 6.9 20 48 35.9 49 98 1751.3 71 6.5 20 45 37.9 47 96 173 1.5 72 6.6 20 48 36.5 47 95 172 1.3 736.5 21 52 36.1 47 95 171 1.3 Mean 6.9 19.6 44.8 38.0 42.0 90.6 172.5 1.7Std dev 0.6 2.5 6.9 5.9 6.3 7.0 13.0 1.3 % rsd 8.9% 12.7% 15.4% 15.6%15.0% 7.8% 7.5% 75.3% Pre-Classified Feed Data (Malvern) EXAMPLE 1(Fine) 7 28 64 27.1 52 97 164 2.2 EXAMPLE 1 (Coarse) 7 26 55 28.8 48 101189 2.5 EXAMPLE 2 (Fine) 7.3 26 59 28.5 49 88 153 1.5 EXAMPLE 2 (Coarse)7 26 59 30 49 93 166 2 EXAMPLE 3 (Fine) 7.1 27 58 27.4 48 87 151 1.7EXAMPLE 3 (Coarse) 7 26 56 29 50 91 157 1.6 Mean of examples 7.1 26.558.5 28.5 49.3 92.8 163.3 1.9 1, 2 & 3 Stdev of Examples 0.1 0.8 3.1 1.11.5 5.4 13.9 0.4 1, 2 & 3 RSD of Examples 1, 2 1.7% 3.2% 5.4% 3.8% 3.1%5.8% 8.5% 20.2% & 3 Mean of Examples 2 7.1 26.3 58.0 28.7 49.0 89.8156.8 1.7 & 3 Std Dev. Of Examples 0.1 0.5 1.4 1.1 0.8 2.8 6.7 0.2 2 & 3RSD of Examples 2 & 3 2.0% 1.9% 2.4% 3.8% 1.7% 3.1% 4.2% 12.7%

An important aspect of the parameters described within the protocolsillustrated in Examples 1 through 3 is that all initial stages are thesame, irrespective of the desired amount of fine lactose in the finalproduct to be manufactured. The varying amounts of fine lactose that aredesired are achieved by combining the appropriate proportions of thecoarse and fines fractions and not to mill “harder” for the lactosebatches that require more fine lactose in the final product. Tables 6and 7 show the particle size for the feed Batch A crystal by bothMalvern and Sympatec, that was used in these trials.

It can be seen from these three examples that all the initial stages aresimilar, if not identical. The only stage at which there is a change isat the blending stage, in which more fine lactose would be added toachieve the required targets at %<4.5 microns.

Tables 6 and 7 show the particle size data for the both coarse and finefeed crystal lactose used in Examples 1, 2 and 3. (Malvern and Sympatec)

TABLE 6 Particle size data of the feed lactose prior to classification -Malvern Malvern Data Feed Batch D10 D50 D90 % < 15 microns “Fine” Feedfor Example 1 57 123 208 2 “Coarse” Feed for Example 1 86 176 284 0.8“Fine” Feed for Example 2 53 114 208 1.14 “Coarse” Feed for Example 2 84162 270 0.7 “Fine” Feed for Example 3 53 114 207 1.02 “Coarse” Feed forExample 3 81 161 274 0.7

TABLE 7 Particle size data of the feed lactose prior to classification -Sympatec Malvern Data Feed Batch D10 D50 D90 % < 4.5 microns “Fine” Feedfor Example 1 40 116 188 2 “Coarse” Feed for Example 1- 63 165 263 1.3“Fine” Feed for Example 2 39 103 180 1.3 “Coarse” Feed for Example 2 68150 239 1.0 “Fine” Feed for Example 3 38 102 177 1.1 “Coarse” Feed forExample 3 65 149 248 1.3

Discussion:

A range of feed lactose has been covered by choosing both coarse andfine feed lactose in each of these three examples. They contain varyingamounts of lactose that would pass through the mill, essentiallyun-milled, and end up in packed product.

In each of the examples 1-3, the majority of these small particles areremoved by a classification process so that the resultant feed materialis much more uniform when presented to the mill. A target was to reducethe amount of lactose particles less than 70 microns to less than 10%.An alternative way of expressing this is that the D10 of the resultinglactose should be greater than 70 microns by Sympatec.

The results from the three examples are shown in Table 8.

TABLE 8 Coarse Fraction from the Crystalline Feed Lactose after initialclassification step - Sympatec Sympatec Data D10 D50 D90 % < 4.5 microns“Fine” Feed for Example 1 82 135 202 0.0 after classification “Coarse”Feed for Example 1 107 177 259 0.0 after classification “Fine” Feed forExample 2- 66 125 202 0.6 after classification “Coarse” Feed for Example2 94 160 240 0.2 after classification (Coarse) “Fine” Feed for Example 367 125 203 0.4 after classification “Coarse” Feed for Example 3 92 158245 0.2 after classification

It can be seen from Table 8 that there were two instances in which thetarget for removing the fine material less than 70 microns was not quiteachieved, although the values of 66 and 67 microns are close enough thatthey are believed to not impact on the outcome of the experiments.

Milling of the Classified Feed

Each of the coarse fractions were then milled to reduce the D50 tobetween 60-70 microns by Malvern. The values from Example 1 indicatedthat slightly harder milling was required, so this was adjusted forExamples 2 and 3.

The results are shown in Table 9 (Malvern) and Table 10 (Sympatec).

TABLE 9 Milled “Coarse” fraction. Particle Size Data by Malvern. MalvernData D10 D50 D90 % < 15 microns “Fine” Feed for Example 1 15 75 152 10.0after milling coarse fraction) “Coarse” Feed for Example 1 13 72 16911.4 after milling coarse fraction) “Fine” Feed for Example 2 15 70 1419.9 after milling coarse fraction) “Coarse” Feed for Example 2 13 66 14511.5 after milling coarse fraction) “Fine” Feed for Example 3 14 64 13310.9 after milling coarse fraction) “Coarse” Feed for Example 3 12 61139 13.1 after milling coarse fraction)

TABLE 10 Milled “Coarse” fraction. Particle Size Data by SympatecSympatec Data D10 D50 D90 % < 4.5 microns “Fine” Feed for Example 1 7.063 140 6.5 after milling coarse fraction) “Coarse” Feed for Example 16.3 55 151 7.3 after milling coarse fraction) “Fine” Feed for Example 27.5 59 127 6.3 after milling coarse fraction) “Coarse” Feed for Example2 6.1 54 132 7.7 after milling coarse fraction) “Fine” Feed for Example3 7.0 55 123 6.7 after milling coarse fraction) “Coarse” Feed forExample 3 5.4 48 125 8.3 after milling coarse fraction)

Classification of the Milled Lactose

The milled lactose was then separated into a coarse and fine fractionusing the same classifier as was used to separate the fine lactose fromthe input feed lactose. The resultant particle size data are shown inTables 11, 12, 13 and 14.

TABLE 11 Fine Fractions after Milling and Classification of the CoarseCrystalline Feed Fraction by Malvern Malvern Data % < 15 D10 D50 D90microns “Fine” Feed for Example 1 7.0 28 64 27.1 Milled/Classified afterclassification “Coarse” Feed for Example 1 7.0 26 55 28.8Milled/Classified after classification “Fine” Feed for Example 2 7.3 2659 28.5 Milled/Classified after classification “Coarse” Feed for Example2 7.0 26 59 30.0 Milled/Classified after classification “Fine” Feed forExample 3 7.1 27 58 27.4 Milled/Classified after classification “Coarse”Feed for Example 3 7.0 26 56 29.0 Milled/Classified after classification

TABLE 12 Coarse Fractions after Milling and Classification of the CoarseCrystalline Feed Fraction by Malvern Malvern Data % < 15 D10 D50 D90microns “Fine” Feed for Example 1 52 97 164 2.2 Milled/Classified afterclassification “Coarse” Feed for Example 1 48 101 189 2.5Milled/Classified after classification “Fine” Feed for Example 2 49 88153 1.5 Milled/Classified after classification “Coarse” Feed for Example2 49 93 166 2.0 Milled/Classified after classification “Fine” Feed forExample 3 48 87 151 1.7 Milled/Classified after classification “Coarse”Feed for Example 3 50 91 157 1.6 Milled/Classified after classification

TABLE 13 Fine Fractions after Milling and Classification of the CoarseCrystalline Feed Fraction by Sympatec Sympatec Data % < 15 D10 D50 D90microns “Fine” Feed for Example 1 4.0 22 57 12.9 Milled/Classified afterclassification “Coarse” Feed for Example 1 4.0 22 56 13.1Milled/Classified after classification “Fine” Feed for Example 2 3.4 2152 13.9 Milled/Classified after classification “Coarse” Feed for Example2 3.0 20 51 15.1 Milled/Classified after classification “Fine” Feed forExample 3 3.5 22 54 13.3 Milled/Classified after classification “Coarse”Feed for Example 3 3.0 21 54 14.5 Milled/Classified after classification

TABLE 14 Coarse Fractions after Milling and Classification of the CoarseCrystalline Feed Fraction by Sympatec Sympatec Data % < 15 D10 D50 D90microns “Fine” Feed for Example 1 39 90 149 2.9 Milled/Classified afterclassification “Coarse” Feed for Example 1 35 93 174 2.9Milled/Classified after classification “Fine” Feed for Example 2 40 83141 2.0 Milled/Classified after classification “Coarse” Feed for Example2 39 88 150 2.5 Milled/Classified after classification “Fine” Feed forExample 3 40 82 139 2.1 Milled/Classified after classification “Coarse”Feed for Example 3 43 87 146 2.1 Milled/Classified after classification

Recombination by Blending

The Examples 1-3 then call for appropriate portions of the fine andcoarse fractions to be blended together so that the resultant blendcontains the required amount of lactose that is less than 4.5 microns.This is in order to achieve the desired value for the FPMass performancefor an inhalable formulation of salmeterol xinafoate and fluticasonepropionate. These target values are listed in the Examples 1-3, and theresults are shown in Tables 15-17.

TABLE 15 Particle Size Data for final packed product from Example 1-Sympatec Sympatec Data D10 D50 D90 % < 4.5 microns “Fine” Feed forExample 1 Target - 3.3% +/− 0.3% 28 89 150 3.4 Target - 6.7% +/− 0.3%, 762 139 6.7 Target - 5.0% +/− 0.3% 11 78 147 5.0 “Coarse” Feed forExample 1 Target - 6.7% +/− 0.3%, 7.3 66 161 6.5 Target - 5.0% +/− 0.3%10 79 167 5.2 Target - 3.3% +/− 0.3% 26 91 172 3.4It can be seen from these Example 1 data that the Sympatec targets at%<4.5 microns were met in every case.

TABLE 16 Particle Size Data for final packed product from Example 2-Sympatec Sympatec Data % < 4.5 D10 D50 D90 microns “Fine” Feed forExample 2-216014 Target - 6.7% +/− 0.3% 7.2 57 125 6.6 Target - 5.0% +/−0.3%, 10 67 131 5.1 Target - 3.3% +/− 0.3% 23 76 135 3.3 “Coarse” Feedfor Example 2- 216017 Target - 6.7% +/− 0.3%, 7.4 59 134 6.4 Target -5.0% +/− 0.3% 11 75 145 5.0 Target - 3.3% +/− 0.3% 24 83 148 3.3

It can be seen from the Example 2 particle size data that the Sympatectargets were met in every case.

TABLE 17 Particle Size Data for final packed product from Example 3-Sympatec Sympatec Data D10 D50 D90 % < 4.5 microns “Fine” Feed forExample 3 Target - 6.3% +/− 0.3% 9.0 63 129 5.5 Target - 6.0% +/− 0.3%10.0 68 132 5.1 Target - 5.5% +/− 0.3% 11 70 133 4.7 “Coarse” Feed forExample 3 Target - 6.3 +/− 0.3% 7.8 66 135 6.2 Target - 6.0 +/− 0.3% 7.969 137 6.1 Target - 5.5 +/− 0.3% 10.0 72 139 5.3

It can be seen from these Example 3 data that the Sympatec targets weremet for the three batches stemming from the coarse feed but not forthose made from the fine feed.

Averages and relative standard deviation values for the D10, D50, D90and the %<15 microns for both the fine and coarse fractions forconventional production were evaluated, compared to the process of theinvention. These are shown in Table 17. All values are Malvern data andthe normal production is all batches of the same lactose productmanufactured over an 18 month period.

TABLE 17 Assessment of Particle size consistency for Example 1, Example2 and Example 3 data d10 d50 d90 % < 15 microns Fine fraction afterClassification - Malvern Current Process approximately 18 months normal6.9 19.6 44.8 38.0 production (mean of 73 batches) Example 1, 2 and 3mean of 6 batches 7.1 26.5 58.5 28.5 RSD Current Process approximately18 months normal 8.9% 12.7% 15.4% 15.6% production- (73 batches) RSDExample 1, 2 and 3- (6 batches) 1.7% 3.2% 5.4% 3.8% Coarse Fractionafter Classification - Malvern Current Process approximately 18 monthsnormal 42.0 90.6 172.5 1.7 production (mean of 73 batches) Example 1, 2and 3 mean of 6 batches 49.3 92.8 163.3 1.9 RSD Current Processapproximately 18 months normal 15.0% 7.8% 7.5% 75.3% production- (73batches) RSD Example 1, 2 and 3- (6 batches) 3.1% 5.8% 8.5% 20.2%

The results in Table 17 show that the particle size of the coarse andfine fractions are more consistent than that obtained during normalproduction, despite the fact that an adjustment was made to the millingsettings between Example 1 and Examples 2 and 3. If Example 1 data iseliminated from the assessment then the variation in particle size iseven less as shown in Table 18.

TABLE 18 Assessment of Example 2 and Example 3 data only-Malvern d10 D50D90 % < 15 microns Fine fraction after Classification - Malvern CurrentProcess approximately 18 months 6.9 19.6 44.8 38.0 normal production(mean of 73 batches) Example 2 and 3 mean of 4 batches 7.1 26.3 58.028.7 RSD Current Process approximately 18 months 8.9% 12.7% 15.4% 15.6%normal production- (73 batches) RSD EXAMPLE 2 and 3- (4 batches) 2.0%1.9% 2.4% 3.8% Coarse Fraction after Classification - Malvern CurrentProcess approximately 18 months 42.0 90.6 172.5 1.7 normal production(mean of 73 batches) Example 2 and 3 approximately 18 months 49.0 89.8156.8 1.7 normal production mean of 4 batches RSD Current Processapproximately 18 months 15.0% 7.8% 7.5% 75.3% normal production- (73batches) RSD Example 2 and 3- (4 batches) 1.7% 3.1% 4.2% 12.7%

Particle Size Profiles for Example 1, Example 2 and Example 3

The full profiles for each of the three pairs of lactose made inExamples 1 and 3 are shown in FIGS. 1-3.

It can be seen that these three pairs of curves are reasonably similar,despite originating from a “coarse” and “fine” feed in each occasion.For a comparison FIG. 4 shows the data form Example 2 overlaid with twonormal production batches of similar lactose. These show the extremes indiffering profiles that can be obtained during normal production.

EXAMPLE 4 Lactose Production

The following example demonstrates the production of lactose suitablefor use in inhalation formulations, which has been produced by a methodthat does not require the combination of any of the fine fraction to thecoarse fraction.

The following experimental method may be employed:

-   -   1. Classify 2 tons of crystalline lactose A so that the majority        of fine crystals <70 microns are removed into the fine fraction.        The remaining coarse fraction must comply with the acceptance        criteria shown in Table 19 below.

TABLE 19 Measurement are by Sympatec %<4.5 microns D10 D50 CoarseFraction <0.2% >70 microns >130 microns

-   -   3. Mill only the coarse fraction of lactose targetting 60        microns +/−3 microns for the D50 of the milled product.    -   4. Using pilot scale blender, separate 300 kgs of the milled        batch into a fine and coarse fraction using the maximum        classifier wheel speed and suitable air flow parameters to        achieve the lowest micron cut point that can be achieved. This        will leave a coarse fraction that contains as much fine lactose        as possible. (Product a)    -   5. Repeat 4 on another 300 kg aliquot of the milled lactose, but        reduce the speed of the classifier wheel and keep the air flow        at the same settings. This will produce a somewhat coarser        coarse fraction. (Product B)    -   6. Repeat 4 again on another 300 kg aliquot of the milled        lactose, but reduce the speed of the classifier wheel further        and keep the air flow at the same settings. This again will        produce an even coarser coarse fraction. (Product C)    -   7. Do not add any of the fine fractions to the coarse fractions,        but blend each of the coarse fractions to ensure homogeneity.        Dispense the blended lactose into 20 kg tie sealed polyethylene        bags, which are then heat sealed into a foil laminate bag.

Pack at least 7×20 kgs boxes of each batch, and record the particle sizedistribution by Sympatec on the final product.

TABLE 20 Results of the Classified Feed Lactose - Coarse Fraction:Sample Number %<4.5 microns D10 D50 1 0% 92.03 155.96 2 0% 93.87 159.5 30% 90.75 156.24 4 0% 93.28 158.26 5 0% 92.53 157.05

It can be seen from the data in Table 20 that the readings comply withthe specifications detailed in Table 19.

Results for the full particle size distribution of the final products A,B & C by Sympatec are in Table 21.

TABLE 21 Sympatec High Size Microns Product A Product B Product C 4.504.26 4.01 3.91 5.50 5.30 4.94 4.80 6.50 6.33 5.86 5.65 7.50 7.36 6.766.48 9.00 8.89 8.10 7.71 11.00 10.92 9.88 9.33 13.00 12.94 11.68 10.9815.50 15.47 13.99 13.11 18.50 18.49 16.83 15.79 21.50 21.47 19.75 18.5925.00 24.91 23.19 21.94 30.00 29.69 28.07 26.79 37.50 36.54 35.18 33.9645.00 43.05 41.93 40.85 52.50 49.24 48.34 47.43 62.50 57.02 56.34 55.6475.00 65.83 65.35 64.89 90.00 74.83 74.48 74.26 105.00 81.95 81.64 81.60125.00 88.81 88.49 88.60 150.00 94.13 93.77 93.97 180.00 97.47 97.0897.30 215.00 99.14 98.78 98.96 255.00 99.77 99.54 99.65 305.00 100.0099.87 99.93 365.00 100.00 100.00 99.98 435.00 100.00 100.00 100.00515.00 100.00 100.00 100.00 615.00 100.00 100.00 100.00 735.00 100.00100.00 100.00 875.00 100.00 100.00 100.00

These data can also be presented graphically as shown in FIG. 8. It canbe seen from FIG. 8 that the amount of lactose present in the region <25microns high size is of the same order as that shown in FIG. 4 which isthat of routine commercial batches used for inhalation grade lactose.Thus, these coarse fractions are believed to be capable of displayingsuitable Fine Particle Mass (FPM) performance to make them useful asinhalation grade lactose.

Conclusions:

All of the trials, Example 1, Example 2 and Example 3 have been assessedfor CI performance at release and upon accelerated ageing at 25 degreesCelsius, 75% relative humidity. The series of Tables 22A, 22B and 22Cshow the initial mean data that were obtained during the stability studyfor Fine Particle Mass (FPMass), Throat, Pre-separator and stage 0,(TP0) and Stages 3+4.

TABLE 22A i Initial Mean Fine Particle Mass Data for 75 μg salmeterolxinafoate (equivalent to 50 μg salmeterol base) and 100 μg fluticasonepropionate formulation using a conventional fine lactose Fine ParticleFine Particle DP Trial Mass (FP) Mass (SX) Example 1 - (fine lactose) exCoarse 28.6 12.4 feed Example 1 - (fine lactose) ex Fine feed 31.8 13.9Example 2 - (fine lactose) ex Coarse 26.3 12.9 feed Example 2 - (finelactose) ex Fine 25.6 12.4 feed Example 3 - (fine lactose) ex Coarse22.7 10.3 feed Example 3 - (fine lactose) ex Fine feed 21.3 10.4

TABLE 22A ii Initial Mean TPO Data for 50 μg salmeterol base/100 μgfluticasone propionate formulation sing a conventional fine lactose DPTrial TPO (FP) TPO (SX) Example 1 - (fine lactose) ex Coarse 64.4 32.9feed Example 1 - (fine lactose) ex Fine 62.0 31.8 feed Example 2 - (finelactose) ex Coarse 65.7 33.0 feed Example 2 - (fine lactose) ex Fine65.9 32.8 feed Example 3 - (fine lactose) ex Coarse 68.8 34.4 feedExample 3 - (fine lactose) ex Fine 70.2 35.4 feed

TABLE 22A iii Initial Mean Stages 3 + 4 Data for 50 μg salmeterolbase/100 μg fluticasone propionate formulation using conventional finelactose DP Trial 3 + 4 (FP) 3 + 4 (SX) Example 1 - fine lactose) exCoarse 15.8 7.0 feed Example 1 - (fine lactose) ex Fine 18.0 8.1 feedExample 2 - (fine lactose) ex Coarse 14.4 7.2 feed Example 2 - (finelactose) ex Fine 13.9 6.9 feed Example 3 - (fine lactose) ex Coarse 11.95.4 feed Example 3 - (fine lactose) ex Fine 11.9 5.7 feed NB.Specifications for Advair 50/100 are: FP FPMass, 21-30; SX FPMass, 9-13FP Stages 3 + 4, 11-19; SX Stages 3 + 4, 4-8 FP TP0, 55-80; SX TP0,28-42

TABLE 22B i Initial Mean Fine Particle Mass Data for 50 μg salmeterolbase/250 μg fluticasone propionate formulation using a conventionalmedium grade lactose Fine Particle Fine DP Trial Mass (FP) Particle Mass(SX) Example 1 - (Medium Lactose) ex 57.8 10.5 Coarse feed Example 1 -(Medium Lactose) ex 55.7 10.4 Fine feed Example 3 - (Medium Lactose) ex68.8 13.3 Coarse feed Example 3 - (Medium Lactose) ex 50.3 9.7 Fine feed

TABLE 22B ii Initial Mean TPO Data for 50 μg salmeterol base/250 μgfluticasone propionate formulation using a medium grade lactose DP TrialTPO (FP) TPO (SX) Example 1 - (Medium Lactose) ex 170.5 34.0 Coarse feedExample 1 - (Medium Lactose) ex 174.8 35.2 Fine feed Example 3 - (MediumLactose) ex 154.7 32.1 Coarse feed Example 3 - (Medium Lactose) ex 168.833.2 Fine feed

TABLE 22B iii Initial Mean Stages 3 + 4 Data for 50 μg salmeterolbase/250 μg fluticasone propionate formulation using a conventionalmedium grade lactose DP Trial Stages 3 + 4 (FP) Stages 3 + 4 (SX)Example 1 - (Medium Lactose) ex 32.7 6.0 Coarse feed Example 1 - (MediumLactose) ex 30.2 5.7 Fine feed Example 3 - (Medium Lactose) ex 40.0 7.8Coarse feed Example 3 - (Medium Lactose) ex 27.2 5.2 Fine feed NB.Specifications for Advair 50/250 are: FP FPMass, 51-75; SX FP Mass, 9-13FP Stages 3 + 4, 29-48; SX Stages 3 + 4, 5-8 FP TP0, 140-200; SX TP0,28-42

TABLE 22C i Initial Mean Fine Particle Mass Data for 50 μg salmeterolbase/500 μg fluticasone propionate formulation using a conventionalcoarse grade lactose Fine Particle Fine DP Trial Mass (FP) Particle Mass(SX) Example 1 - (Coarse Lactose) ex 74.9 7.1 Coarse feed Example 1 -(Coarse Lactose) ex 85.0 7.9 Fine feed Example 3 - (Coarse Lactose) ex125.7 12.7 Coarse feed Example 3 - (Coarse Lactose) ex 123.5 11.9 Finefeed

TABLE 22C ii Initial Mean TPO Data for 50 μg salmeterol base/500 μgfluticasone propionate formulation using a conventional coarse gradelactose DP Trial TPO (FP) TPO (SX) Example 1 - (Coarse Lactose) ex 399.239.3 Coarse feed Example 1 - (Coarse Lactose) ex 392.1 38.8 Fine feedExample 3 - (Coarse Lactose) ex 293.1 33.4 Coarse feed Example 3 -(Coarse Lactose) ex 323.0 32.3 Fine feed

TABLE 22C iii Initial Mean Stages 3 + 4 Data for 50 μg salmeterolbase/500 μg fluticasone propionate formulation using a conventionalcoarse grade lactose DP Trial Stages 3 + 4 (FP) Stages 3 + 4 (SX)Example 1 - (Coarse Lactose) ex 42.4 4.0 Coarse feed Example 1 - (CoarseLactose) ex 49.0 4.5 Fine feed Example 3 - (Coarse Lactose) ex 74.2 7.5Coarse feed Example 3 - (Coarse Lactose) ex 78.5 7.6 Fine feed NB.Specifications for Advair 50/500 are: FP FPMass, 106-150; SX FPMass,10-14. FP Stages 3 + 4, 60-95; SX Stages 3 + 4, 5-9. FP TP0, 290-400; SXTP0, 28-42.

Taking all of the factors into account, the data suggests that thepre-classification of the feed crystal to remove small lactose crystalsbelow approximately 70 microns does not appear to significantly alterthe performance ex device when compared to the normal method of lactoseproduction. Additionally, and advantageously, the invention offers aprocess for forming lactose which provides improved control of particlesize distribution relative to conventional processes.

EXAMPLE 5 Stability Tests

Stability data for various formulations each containing 100 μgfluticasone propionate and 50 μg salmeterol base along with lactoseformed in accordance with the invention were evaluated under nakedconditions at 25° C. and 75 percent Relative Humidity. As shown in Table23, such data were evaluated at different time points. As shown,formulations made from the process according to the invention exhibitgood stability characteristics.

TABLE 23 SX Fine FP Fine Advair Experiment Conditions: Time pointParticle Particle Strength Number Temp/% RH (months) Mass Mass 100/50 1initial 12.38 28.55 100/50 1 25/75 0.5 12.53 27.74 100/50 1 25/75 1.012.87 28.72 100/50 1 25/75 1.5 12.22 27.34 100/50 1 25/75 2.0 12.0527.61 100/50 1 25/75 3.0 11.45 25.77 100/50 1 initial 13.87 31.81 100/501 25/75 0.5 13.14 30.60 100/50 1 25/75 1.0 12.97 29.29 100/50 1 25/751.5 13.11 29.61 100/50 1 25/75 2.0 13.23 30.77 100/50 1 25/75 3.0 12.2927.83 100/50 2 initial 12.42 25.60 100/50 2 25/75 2.0 11.59 24.64 100/502 25/75 3.0 11.34 24.24 100/50 2 initial 12.92 26.31 100/50 2 25/75 2.011.80 24.88 100/50 2 25/75 3.0 10.84 23.04 100/50 3 initial 10.27 22.69100/50 3 25/75 0.5 11.65 24.27 100/50 3 25/75 1.0 10.84 24.92 100/50 325/75 1.5 10.59 22.21 100/50 3 25/75 3.0 10.23 21.86 100/50 3 initial10.43 21.32 100/50 3 25/75 0.5 9.06 19.21 100/50 3 25/75 1.0 10.05 21.11100/50 3 25/75 1.5 8.61 18.38 100/50 3 25/75 3.0 8.21 17.45

EXAMPLES 6-8 Stability Studies

Examples 6-8 set forth various pharmaceutical formulations for which thestability was evaluated. Batches 01, 02 and 03 were processed inaccordance with the present invention by employing a pre-classificationstage prior to proceeding by conventional manufacturing used for makingAdvair® made commercially available by GlaxoSmithkline of Brenfford,United Kingdom. Batch 04 was made using an Advair® manufacturingprocess. In Tables 24-28, the symbol “T” indicates that the particlesize distribution of salmeterol xinafoate and fluticasone propionatewere evaluated by Cascade Impaction according to Method STM-195.

Tables 29-31 illustrate the average change of drug recovered in stages 1to 5 as a percentage, normalising the results to take into account thetotal drug recovery for each device. The change is determined betweenthe initial and final time points as defined in the protocol and iscalculated according to the following equation:

${\frac{\begin{matrix}{{Stage}\mspace{14mu} 1\mspace{14mu} {to}\mspace{14mu} 5} \\{{recovery}\mspace{14mu} {at}\mspace{14mu} {initial}}\end{matrix}}{\begin{matrix}{{Total}\mspace{14mu} {recovery}} \\{{at}\mspace{14mu} {initial}\mspace{14mu} {point}}\end{matrix}} \times 100} - {\frac{\begin{matrix}{{{Stage}\mspace{14mu} 1\mspace{14mu} {to}\mspace{14mu} 5\mspace{14mu} {recovery}}\mspace{14mu}} \\{{at}\mspace{14mu} {final}\mspace{14mu} {time}\mspace{14mu} {point}}\end{matrix}}{{Total}\mspace{14mu} {recovery}\mspace{14mu} {at}\mspace{14mu} {final}\mspace{14mu} {time}} \times 100}$

Tables 32-34 provide summaries of the stability studies that are setforth in Tables 35 to 130. These tables illustrate Cascade Impactionresults.

Referring to the tables that follow:

“500/50 μg” refers to a formulation containing 50 μg salmeterol base and500 μg fluticasone propionate in lactose.

“250/50 μg” refers to a formulation containing 50 μg salmeterol base and250 μg fluticasone propionate in lactose.

“100/50 μg” refers to a formulation containing 50 μg salmeterol base and100 μg fluticasone propionate in lactose.

“MDPI” refers to a multidose dry powder inhaler.

A* refers to in-use testing. Devices to be removed from 25° C./60% RHstorage and overwrappers to be removed. Samples to be returned tostorage at 25° C./75% RH. See Tables 25 and 27.

In Tables 32-34, Batches A, E and I correspond to batch 01. Batches B, Fand J correspond to batch 02. Batches C, G and K correspond to batch 03.Batches D, H and L correspond to batch 04.

-   -   Tables 24-25: Testing Protocols for 100/50 μg

TABLE 24 Storage condition Storage time (months) ° C./% RH Initial 0.5 11.5 3 6 9 12 14 15 T 25/60 Wrapped T T T T T A* T 25/75 Naked T T T T

TABLE 25 Storage condition Storage time (months) ° C./% RH 0 0.5 1 1.5[Total time on test] [14] [14.5] [15] [15.5] 25/75 Naked T T T T

TABLE 26 Testing Protocol for 250/50 μg Storage condition Storage time(months) ° C./% RH Initial 0.5 1 1.5 3 6 9 12 17 18 T 25/60 Wrapped T TT T T A* T 25/75 Naked T T T T

Tables 27-28 Testing Protocol for 500/50 μg

TABLE 27 Storage condition Storage time (months) ° C./% RH 0 0.5 1 1.5[Total time on test] [17] [17.5] [18] [18.5] 25/75 Naked T T T T Storagecondition Storage time (months) ° C./% RH Initial 0.5 1 1.5 3 6 9 12 1718 T 25/60 Wrapped T T T T T A* T 25/75 Naked T T T T

TABLE 28 Storage condition Storage time (months) ° C./% RH 0 0.5 1 1.5[Total time on test] [17] [17.5] [18] [18.5] 25/75 Naked T T T T

TABLE 29 Average Change of Drug Recovered in Stages 1-5 (100/50 μg)Batch Storage Condition/Drug 01 02 03 04 25° C./60% RH Wrapped SX −5 −5−5 −5 25° C./60% RH Wrapped FP −5 −5 −6 −6 25° C./75% RH Naked SX −7 −3−4 −4 25° C./75% RH Naked FP −7 −4 −6 −5 25° C./75% RH Naked Aged In UseSX 0 +1 −2 −1 25° C./75% RH Naked Aged In Use FP 0 0 −2 −1

TABLE 30 Average Change of Drug Recovered in Stages 1-5 (250/50 μg)Batch Storage Condition/Drug 01 02 03 04 25° C./60% RH Wrapped SX −5 −4−6 −3 25° C./60% RH Wrapped FP −6 −5 −7 −4 25° C./75% RH Naked SX −5 −5−4 −4 25° C./75% RH Naked FP −5 −5 −4 −3 25° C./75% RH Naked Aged In UseSX +1 0 −2 0 25° C./75% RH Naked Aged In Use FP 0 0 −2 −1

TABLE 31 Average Change of Drug Recovered in Stages 1-5 (500/50 μg)Batch Storage Condition/Drug 01 02 03 04 25° C./60% RH Wrapped SX −5 −3−4 −3 25° C./60% RH Wrapped FP −5 −3 −4 −3 25° C./75% RH Naked SX −3 −30 −4 25° C./75% RH Naked FP −3 −3 −1 −4 25° C./75% RH Naked Aged In UseSX +1 +1 0 +2 25° C./75% RH Naked Aged In Use FP +1 0 0 +1

TABLE 32 Summary of Stability Studies for 100/50 μg MDPI (Example 6)Stability data table number (s) 35 to 43 44 to 50 51 to 58 59 to 66Batch designation (methodology) A B C D Lactose batch designation DD DDEE FF % of lactose fines  6.7  6.7  7.0   5.6 Data presented 25/60W 15M15M 15M 15M 25/75N  3M  3M  3M  3M 25/75N 1.5M  1.5M  1.5M  1.5M  AgedIn Use Specification failures 25/60W 1* 1* 1* 0 Specification failures25/75N 3* 5* 3* 0 Specification failures 25/75N 1* 0  1* 0 Aged In Use

TABLE 33 Summary of Stability Studies for 250/50 μg MDPI (Example 7)Stability data table number (s) 67 to 74 75 to 82 83 to 90 91 to 98Batch designation (methodology) E F G H Lactose batch designation AA AABB CC % of lactose fines   5.2   5.2  6.4   4.7 Data presented 25/60W18M 18M 18M 18M 25/75N  3M  3M  3M  3M 25/75N 1.5M  1.5M  1.5M  1.5M Aged In Use Specification failures 25/60W 0  1* 3* 0 Specificationfailures 25/75N  2* 0 4* 0 Specification failures 25/75N 0 0 0  0 AgedIn Use

TABLE 34 Summary of Stability Studies for 500/50 μg MDPI (Example 8)Stability data table number (s) 99 to 106 107 to 114 115 to 122 123 to130 Batch designation I J K L (methodology) Lactose batch GG GG GG HHdesignation % of lactose fines   4.5   4.5   4.5   4.2 Data presented25/60W 18M 18M 18M 18M 25/75N  3M  3M  3M  3M 25/75N 1.5M  1.5M  1.5M 1.5M  Aged In Use Specification failures 2 0 1 5 25/60W Specificationfailures 0 0 0 2 25/75N Specification failures 0 0 0 4 25/75N Aged InUse

TABLE 35 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: A Storage condition 25° C./60% RH TestingComplete End of life Storage Time Specification Initial 1 Month 3 Months6 Months Particle Size Distribution by Cascade  7 to 13 15, 15 12, 1210, 12 12, 11 Impaction Salmeterol Sum of stages 14, 14 13, 13 11, 1211, 11 1-5 (μg per blister) Individual Particle Size Distribution byCascade 3 to 8 8, 8 7, 7 5, 6 6, 6 Impaction Salmeterol Sum of stages 8,8 7, 7 6, 6 6, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 33, 33 32, 32 30, 34 32, 33 ImpactionSalmeterol Sum of stages 33, 33 34, 34 32, 34 31, 34 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.2 0.0, 0.1 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 36 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: A Storage condition 25° C./60% RH TestingComplete End of life Storage Time Specification Initial 9 months 12months 15 months Particle Size Distribution by Cascade  7 to 13 15, 1511, 12 12, 11 12, 11 Impaction Salmeterol Sum of stages 14, 14 12, 1211, 12 11, 12 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 3 to 8 8, 8 5, 6 6, 5 6, 6 Impaction Salmeterol Sum of stages8, 8 6, 6 5, 6 6, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 33, 33 34, 35 35, 33 35, 33 ImpactionSalmeterol Sum of stages 33, 33 34, 33 35, 34 34, 34 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.0 0.1, 0.1 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.2 0.0, 0.0 0.1, 0.1 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 37 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: A Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 15 to 30 35, 3429, 29 25, 28 28, 26 Impaction Fluticasone Propionate 33, 33 30, 30 26,28 25, 25 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  6 to 18 20, 20 16, 16 12, 14 15, 14 ImpactionFluticasone Propionate 18, 19 17, 17 13, 14 14, 12 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8064, 63 61, 62 58, 65 62, 64 Impaction Fluticasone Propionate 63, 63 65,66 62, 65 61, 66 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual

TABLE 38 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: A Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 15 months Particle Size Distribution by Cascade 15 to 30 35, 3426, 29 28, 27 29, 27 Impaction Fluticasone Propionate 33, 33 28, 28 27,28 27, 29 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  6 to 18 20, 20 13, 14 13, 13 15, 14 ImpactionFluticasone Propionate 18, 19 15, 14 12, 13 13, 14 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8064, 63 66, 67 66, 64 68, 64 Impaction Fluticasone Propionate 63, 63 65,64 68, 66 66, 67 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual

TABLE 39 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: A Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1315, 15 13, 12 11, 11 14, 12 11, 11 Impaction Salmeterol Sum of stages14, 14 14, 13 12, 11 12, 14 10, 11 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 4 to 8 8, 8 7, 6 6, 6 7, 7 6, 6Impaction Salmeterol Sum of stages 8, 8 8, 8 7, 6 6, 7 5, 6 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 28 to 42 33,33 34, 33 32, 33 34, 33 36, 35 Impaction Salmeterol Sum of stages 33, 3334, 34 33, 33 34, 35 33, 35 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.1, 0.1 0.2, 0.1 0.1, 0.1 0.0, 0.00.0, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.2 0.1, 0.1 0.1, 0.10.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual Note: NGT = NotGreater Than

TABLE 40 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: A Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade 17 to 3035, 34 31, 27 29, 27 32, 29 28, 26 Impaction Fluticasone Propionate 33,33 33, 31 30, 26 29, 32 25, 27 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade  9 to 19 20, 20 18, 1415, 14 17, 16 15, 14 Impaction Fluticasone Propionate 18, 19 18, 18 17,13 15, 17 12, 14 Sum of stages 3-4 (μg per blister) Individual ParticleSize Distribution by Cascade 55 to 80 64, 63 65, 62 63, 64 65, 63 69, 68Impaction Fluticasone Propionate 63, 63 65, 64 65, 66 65, 67 65, 69 Sumof stages TP0 (μg per blister) Individual Particle Size Distribution byCascade NGT 1 0, 0 0, 0 0, 0 0, 0 0, 0 Impaction Fluticasone Propionate0, 0 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μg per blister)Individual

TABLE 41 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 14months Packed Batch Number: A Storage condition 25° C./75% RH TestingComplete End of life Storage Time Specification Initial 2 weeks 1 month1.5 months Particle Size Distribution by Cascade  7 to 13 12, 12 12, 1212, 11 12, 11 Impaction Salmeterol Sum of stages 13, 12 11, 12 11, 1111, 12 1-5 (μg per blister) Individual Particle Size Distribution byCascade 3 to 8 6, 6 6, 7 5, 5 6, 6 Impaction Salmeterol Sum of stages 6,6 6, 6 5, 5 5, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 35, 36 33, 34 33, 33 35, 34 ImpactionSalmeterol Sum of stages 36, 36 33, 34 32, 34 33, 34 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.1, 0.1 0.1, 0.1 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.1 0.1, 0.1 0.1, 0.1 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 42 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 14months (cont'd) Packed Batch Number: A Storage condition 25° C./75% RHTesting Complete End of life Storage Time Test Specification Initial 2weeks 1 month 1.5 months Particle Size Distribution by Cascade 15 to 3028, 29 30, 28 28, 27 28, 28 Impaction Fluticasone Propionate 31, 28 27,28 25, 26 27, 29 Sum of stages 1-5 (μg per blister) Individual ParticleSize Distribution by Cascade  6 to 18 14, 15 15, 16 13, 13 14, 14Impaction Fluticasone Propionate 15, 14 14, 14 12, 12 13, 14 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 55 to 80 67, 67 65, 66 65, 64 68, 65 Impaction FluticasonePropionate 68, 69 65, 65 62, 66 64, 67 Sum of stages TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 1 0, 0 0,0 0, 0 0, 0 Impaction Fluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum ofstages 6, 7 & F (μg per blister) Individual

TABLE 43 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: A Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 7 to 13 14, 13 12,13 12, 11 10, 10 Impaction Salmeterol Sum of stages 15, 14 12, 12 12, 1211, 12 1-5 (μg per blister) Individual Particle Size Distribution byCascade 3 to 8 8, 7 6, 6 6, 6 5, 5 Impaction Salmeterol Sum of stages 8,8 7, 6 6, 6 6, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 33, 34 35, 36 34, 34 33, 33 ImpactionSalmeterol Sum of stages 36, 33 34, 35 35, 35 33, 35 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.2,0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.2 0.1, 0.1 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 44 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: B Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 15 months Particle Size Distribution by Cascade  7 to 13 14, 1312, 13 12, 12 11, 12 Impaction Salmeterol Sum of stages 15, 14 13, 1212, 11 11, 10 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 3 to 8 8, 7 6, 6 6, 6 5, 6 Impaction Salmeterol Sum of stages8, 8 6, 6 6, 6 5, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 33, 34 32, 34 32, 33 35, 34 ImpactionSalmeterol Sum of stages 36, 33 32, 33 34, 31 33, 35 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.2,0.1 0.0, 0.0 0.1, 0.1 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.2 0.1, 0.1 0.1, 0.1 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 45 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: B Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 15 to 30 34, 3029, 30 28, 27 23, 25 Impaction Fluticasone Propionate 35, 33 29, 29 28,28 27, 28 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  6 to 18 18, 15 14, 15 15, 13 11, 12 ImpactionFluticasone Propionate 18, 18 15, 15 13, 14 14, 14 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8063, 66 66, 69 66, 65 64, 63 Impaction Fluticasone Propionate 68, 62 65,66 67, 66 64, 67 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual

TABLE 46 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: B Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 15 months Particle Size Distribution by Cascade 15 to 30 34, 3029, 30 26, 28 28, 28 Impaction Fluticasone Propionate 35, 33 30, 29 29,26 27, 24 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  6 to 18 18, 15 15, 15 14, 14 13, 14 ImpactionFluticasone Propionate 18, 18 14, 15 14, 14 13, 12 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8063, 66 62, 66 61, 64 68, 65 Impaction Fluticasone Propionate 68, 62 62,64 67, 62 65, 68 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual Note: NGT = Not Greater Than

TABLE 47 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: B Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1314, 13 13, 13 13, 12 13, 11 12, 12 Impaction Salmeterol Sum of stages15, 14 13, 13 12, 11 13, 12 14, 12 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 4 to 8 8, 7 7, 7 7, 7 7, 6 6, 6Impaction Salmeterol Sum of stages 8, 8 7, 7 6, 6 7, 6 7, 6 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 28 to 42 33,34 33, 32 34, 35 35, 30 35, 35 Impaction Salmeterol Sum of stages 36, 3334, 33 34, 34 34, 30 36, 35 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.2, 0.1 0.1, 0.1 0.1, 0.1 0.0, 0.00.0, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.2 0.1, 0.1 0.1, 0.10.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 48 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: B Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade 17 to 3034, 30 31, 31 31, 29 31, 27 28, 28 Impaction Fluticasone Propionate 35,33 31, 30 28, 28 31, 29 32, 28 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade  9 to 19 18, 15 16, 1717, 16 16, 14 13, 14 Impaction Fluticasone Propionate 18, 18 17, 16 16,15 16, 15 16, 13 Sum of stages 3-4 (μg per blister) Individual ParticleSize Distribution by Cascade 55 to 80 63, 66 63, 61 65, 67 67, 57 67, 68Impaction Fluticasone Propionate 68, 62 63, 62 66, 66 66, 58 70, 66 Sumof stages TP0 (μg per blister) Individual Particle Size Distribution byCascade NGT 1 0, 0 0, 0 0, 0 0, 0 0, 0 Impaction Fluticasone Propionate0, 0 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μg per blister)Individual

TABLE 49 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 14months Packed Batch Number: B Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade  7 to 13 12, 1112, 12 11, 12 11, 12 Impaction Salmeterol Sum of stages 11, 11 11, 1111, 12 11, 12 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 3 to 8 6, 5 6, 6 5, 6 5, 6 Impaction Salmeterol Sum of stages6, 5 5, 5 6, 6 5, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 36, 36 35, 34 34, 35 32, 34 ImpactionSalmeterol Sum of stages 31, 35 33, 34 29, 33 34, 36 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.1 0.1, 0.1 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.1 0.1, 0.1 0.1, 0.1 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 50 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 14months Packed Batch Number: B Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade 15 to 30 27, 2728, 29 26, 29 25, 28 Impaction Fluticasone Propionate 27, 26 26, 27 28,28 26, 29 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  6 to 18 14, 13 13, 14 13, 14 12, 13 ImpactionFluticasone Propionate 14, 13 13, 13 13, 14 12, 14 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8068, 69 68, 66 64, 68 62, 67 Impaction Fluticasone Propionate 59, 68 64,66 56, 65 67, 70 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual

TABLE 51 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: C Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  7 to 13 16, 1413, 12 12, 12 12, 12 Impaction Salmeterol Sum of stages 14, 15 12, 1212, 12 13, 12 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 4 to 8 9, 8 7, 6 6, 6 6, 7 Impaction Salmeterol Sum of stages8, 8 6, 6 6, 6 6, 7 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 33, 33 33, 34 34, 35 34, 32 ImpactionSalmeterol Sum of stages 32, 34 34, 34 34, 35 34, 34 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.2,0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.2 0.1, 0.1 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 52 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: C Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 15 months Particle Size Distribution by Cascade  7 to 13 16, 1412, 11 12, 12 12, 12 Impaction Salmeterol Sum of stages 14, 15 11, 1113, 12 12, 11 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 4 to 8 9, 8 6, 6 6, 6 6, 6 Impaction Salmeterol Sum of stages8, 8 5, 6 6, 6 6, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 33, 33 32, 33 36, 37 34, 33 ImpactionSalmeterol Sum of stages 32, 34 32, 33 34, 30 33, 33 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.2,0.1 0.0, 0.0 0.1, 0.1 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.2 0.0, 0.1 0.1, 0.1 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 53 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: C Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 17 to 30 36, 3229, 28 28, 28 29, 29 Impaction Fluticasone Propionate 33, 35 29, 28 28,28 30, 30 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  9 to 19 20, 18 15, 14 14, 14 14, 16 ImpactionFluticasone Propionate 17, 20 14, 14 14, 14 15, 15 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8059, 61 64, 63 64, 66 65, 63 Impaction Fluticasone Propionate 59, 62 63,64 65, 66 67, 65 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual

TABLE 54 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: C Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 15 months Particle Size Distribution by Cascade 17 to 30 36, 3228, 26 28, 28 28, 28 Impaction Fluticasone Propionate 33, 35 25, 27 29,29 27, 27 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  9 to 19 20, 18 14, 13 14, 15 13, 14 ImpactionFluticasone Propionate 17, 20 12, 13 15, 15 13, 13 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8059, 61 61, 62 67, 71 65, 64 Impaction Fluticasone Propionate 59, 62 64,64 65, 59 63, 64 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual

TABLE 55 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: C Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1316, 14 14, 13 12, 12 13, 13 12, 12 Impaction Salmeterol Sum of stages14, 15 13, 13 12, 13 13, 14 12, 13 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 4 to 8 9, 8 8, 7 7, 7 7, 7 6, 6Impaction Salmeterol Sum of stages 8, 8 7, 7 7, 7 7, 7 6, 6 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 28 to 42 33,33 34, 35 34, 34 33, 32 35, 34 Impaction Salmeterol Sum of stages 32, 3434, 34 35, 35 35, 34 34, 34 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.2, 0.1 0.1, 0.1 0.1, 0.1 0.0, 0.00.0, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.2 0.1, 0.2 0.1, 0.10.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 56 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: C Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade 17 to 3036, 32 33, 31 29, 29 31, 29 28, 27 Impaction Fluticasone Propionate 33,35 31, 30 28, 30 31, 32 28, 29 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade  9 to 19 20, 18 17, 1615, 16 16, 15 13, 13 Impaction Fluticasone Propionate 17, 20 16, 16 15,16 16, 17 14, 15 Sum of stages 3-4 (μg per blister) Individual ParticleSize Distribution by Cascade 55 to 80 59, 61 64, 65 65, 64 62, 60 65, 70Impaction Fluticasone Propionate 59, 62 63, 63 67, 66 65, 68 64, 66 Sumof stages TP0 (μg per blister) Individual Particle Size Distribution byCascade NGT 1 0, 0 0, 0 0, 0 0, 0 0, 0 Impaction Fluticasone Propionate0, 0 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μg per blister)Individual

TABLE 57 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 14months Packed Batch Number: C Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade 7 to 13 12, 1212, 12 11, 12 12, 11 Impaction Salmeterol Sum of stages 11, 16 12, 1212, 12 11, 12 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 3 to 8 6, 6 6, 6 5, 6 6, 5 Impaction Salmeterol Sum of stages5, 7 6, 6 6, 6 5, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 34, 35 34, 35 33, 33 34, 35 ImpactionSalmeterol Sum of stages 32, 34 32, 34 33, 33 35, 35 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.1, 0.1 0.1, 0.0 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.1 0.1, 0.1 0.1, 0.0 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 58 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 14months Packed Batch Number: C Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade 15 to 30 29, 2827, 29 26, 27 28, 27 Impaction Fluticasone Propionate 27, 30 28, 27 28,28 25, 27 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  6 to 18 15, 14 13, 14 13, 13 14, 13 ImpactionFluticasone Propionate 13, 15 15, 14 14, 13 12, 13 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8068, 66 67, 67 61, 64 66, 66 Impaction Fluticasone Propionate 63, 66 65,64 64, 64 68, 66 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual

TABLE 59 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: D Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  7 to 13 12, 1111, 10 10, 10  9, 10 Impaction Salmeterol Sum of stages 12, 11 10, 1110, 9   9, 10 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 3 to 8 6, 6 5, 5 5, 5 5, 5 Impaction Salmeterol Sum of stages6, 6 5, 6 5, 5 4, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 36, 36 36, 38 38, 38 37, 37 ImpactionSalmeterol Sum of stages 36, 36 36, 35 38, 37 35, 38 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) IndividualNote: NGT = Not Greater Than

TABLE 60 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: D Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 15 months Particle Size Distribution by Cascade  7 to 13 12, 1110, 9  9, 9 9, 9 Impaction Salmeterol Sum of stages 12, 11 10, 10 10, 9 9, 8 1-5 (μg per blister) Individual Particle Size Distribution byCascade 3 to 8 6, 6 5, 4 4, 4 4, 4 Impaction Salmeterol Sum of stages 6,6 5, 5 4, 3 4, 3 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 36, 36 36, 37 39, 38 37, 35 ImpactionSalmeterol Sum of stages 36, 36 37, 37 39, 39 37, 36 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.0 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.1 0.0, 0.0 0.1, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 61 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: D Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 15 to 30 28, 2626, 25 24, 24 22, 24 Impaction Fluticasone Propionate 28, 26 23, 25 24,23 21, 23 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  6 to 18 15, 14 13, 12 12, 12 11, 11 ImpactionFluticasone Propionate 15, 14 12, 13 12, 11  9, 11 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8068, 68 70, 72 73, 74 71, 72 Impaction Fluticasone Propionate 68, 69 70,66 73, 71 68, 74 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual

TABLE 62 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoverwrap Packed Batch Number: D Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 15 months Particle Size Distribution by Cascade 15 to 30 28, 2624, 22 20, 20 21, 21 Impaction Fluticasone Propionate 28, 26 23, 23 23,20 21, 19 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade  6 to 18 15, 14 11, 10 8, 9 10, 9  ImpactionFluticasone Propionate 15, 14 12, 11 10, 8  9, 8 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 55 to 8068, 68 71, 71 74, 73 72, 69 Impaction Fluticasone Propionate 68, 69 73,71 76, 76 73, 71 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 1 0, 0 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μgper blister) Individual

TABLE 63 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: D Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1312, 11 10, 11 11, 11 11, 10 10, 9  Impaction Salmeterol Sum of stages12, 11 11, 11 11, 11 11, 11 9, 9 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 4 to 8 6, 6 5, 6 6, 6 6, 5 5, 5Impaction Salmeterol Sum of stages 6, 6 5, 5 6, 5 6, 6 5, 5 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 28 to 42 36,36 36, 36 37, 36 35, 32 39, 38 Impaction Salmeterol Sum of stages 36, 3637, 38 37, 35 33, 36 37, 37 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.1, 0.1 0.1, 0.1 0.1, 0.1 0.0, 0.00.0, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.1 0.1, 0.1 0.1, 0.10.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 64 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: D Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade 17 to 3028, 26 24, 26 26, 26 25, 25 23, 22 Impaction Fluticasone Propionate 28,26 25, 25 27, 25 25, 26 22, 23 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade  9 to 19 15, 14 12, 1414, 14 13, 13 12, 11 Impaction Fluticasone Propionate 15, 14 13, 13 14,13 14, 14 11, 11 Sum of stages 3-4 (μg per blister) Individual ParticleSize Distribution by Cascade 55 to 80 68, 68 69, 69 71, 69 68, 62 75, 74Impaction Fluticasone Propionate 68, 69 71, 71 71, 67 67, 69 72, 71 Sumof stages TP0 (μg per blister) Individual Particle Size Distribution byCascade NGT 1 0, 0 0, 0 0, 0 0, 0 0, 0 Impaction Fluticasone Propionate0, 0 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F (μg per blister)Individual

TABLE 65 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 14months Packed Batch Number: D Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 0.5 Months1 Month 1.5 Months Particle Size Distribution by Cascade  7 to 13  9, 10 9, 10  9, 10 8, 9 Impaction Salmeterol Sum of stages 10, 9  10, 9  9, 89, 9 1-5 (μg per blister) Individual Particle Size Distribution byCascade 3 to 8 4, 5 4, 5 4, 5 4, 4 Impaction Salmeterol Sum of stages 5,5 4, 4 4, 3 4, 4 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 35, 37 39, 38 37, 38 32, 38 ImpactionSalmeterol Sum of stages 37, 36 38, 38 36, 36 34, 37 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.1, 0.1 0.0, 0.1 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.1 0.1, 0.1 0.1, 0.0 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 66 Stability data for DISKUS ® 100/50 μg 60 Dose Product withoutoverwrap (Cont'd) Samples previously stored at 25° C./60% RH withoverwrap for 14 months Packed Batch Number: D Storage condition 25°C./75% RH Testing Complete End of life Storage Time Test SpecificationInitial 0.5 Months 1 Month 1.5 Months Particle Size Distribution byCascade 15 to 30 22, 23 22, 24 21, 23 21, 22 Impaction FluticasonePropionate 23, 22 23, 23 22, 20 21, 21 Sum of stages 1-5 (μg perblister) Individual Particle Size Distribution by Cascade  6 to 18 10,11 10, 11 9, 11 9, 10 Impaction Fluticasone Propionate 11, 11 11, 10 10,8 10, 9 Sum of stages 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 55 to 80 68, 72 76, 76 72, 73 65, 74 ImpactionFluticasone Propionate 72, 71 75, 74 70, 70 66, 73 Sum of stages TP0 (μgper blister) Individual Particle Size Distribution by Cascade NGT 1 0, 00, 0 0, 0 0, 0 Impaction Fluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sumof stages 6, 7 & F (μg per blister) Individual

TABLE 67 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: E Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 month 3months 6 months Particle Size Distribution by Cascade  7 to 13 12, 1111, 11 10, 10 10, 8 Impaction Salmeterol Sum of stages 12, 12 10, 11 11,11 9, 9 1-5 (μg per blister) Individual Particle Size Distribution byCascade 3 to 8 7, 6 6, 5 5, 6 5, 4 Impaction Salmeterol Sum of stages 7,7 5, 6 6, 6 5, 4 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 33, 32 36, 37 35, 34 37, 35 ImpactionSalmeterol Sum of stages 34, 34 36, 36 35, 36 33, 35 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 6, 7 &F (μg per blister) 0.1, 0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 Individual

TABLE 68 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: E Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 18 months Particle Size Distribution by Cascade  7 to 13 12, 1110, 10 11, 10 10, 9 Impaction Salmeterol Sum of stages 12, 12 9, 11 10,11 9, 9 1-5 (μg per blister) Individual Particle Size Distribution byCascade 3 to 8 7, 6 5, 5 5, 5 5, 4 Impaction Salmeterol Sum of stages 7,7 5, 6 5, 5 4, 4 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 33, 32 36, 35 37, 35 36, 34 ImpactionSalmeterol Sum of stages 34, 34 33, 36 34, 37 34, 36 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.0 0.1, 0.1 0.1, 0.0 Impaction Salmeterol Sum of stages 0.1,0.1 0.0, 0.0 0.1, 0.1 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 69 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: E Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 month 3months 6 months Particle Size Distribution by Cascade 42 to 73 66, 6162, 61 55, 59 58, 48 Impaction Fluticasone Propionate 67, 69 59, 62 63,63 54, 51 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade 19 to 45 39, 34 32, 31 29, 32 29, 22 ImpactionFluticasone Propionate 39, 41 30, 32 34, 34 27, 26 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 140 to 200159, 154 173, 177 169, 165 181, 171 Impaction Fluticasone Propionate161, 161 170, 174 169, 173 163, 168 Sum of stages TP0 (μg per blister)Individual Particle Size Distribution by Cascade <2 0, 0 0, 0 0, 0 0, 0Impaction Fluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7& F (μg per blister) Individual

TABLE 70 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: E Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 18 months Particle Size Distribution by Cascade 42 to 73 66, 6160, 55 64, 57 56, 50 Impaction Fluticasone Propionate 67, 69 54, 62 55,61 54, 54 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade 19 to 45 39, 34 30, 27 31, 28 26, 23 ImpactionFluticasone Propionate 39, 41 28, 32 27, 29 25, 24 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade ImpactionFluticasone Propionate 140 to 200 159, 154 177, 169 176, 179 174, 165Sum of stages TP0 (μg per blister) 161, 161 162, 173 167, 180 178, 177Individual Particle Size Distribution by Cascade <2 0, 0 0, 0 0, 0 0, 0Impaction Fluticasone Propionate 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7& F (μg per blister) Individual

TABLE 71 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: E Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1month 1.5 months 3 months Particle Size Distribution by Cascade  7 to 1312, 11 12, 14 11, 11 12, 11 10, 10 Impaction Salmeterol Sum of stages12, 12 11, 12 10, 11 11, 11 10, 10 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 3 to 8 7, 6 6, 8 5, 6 7, 6 5, 5Impaction Salmeterol Sum of stages 7, 7 6, 6 5, 6 6, 6 5, 5 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 28 to 42 33,32 35, 44 35, 36 36, 34 37, 36 Impaction Salmeterol Sum of stages 34, 3434, 36 35, 36 36, 35 36, 37 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.1, 0.1 0.0, 0.0 0.0, 0.0 0.0, 0.00.0, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.1 0.0, 0.0 0.0, 0.00.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 72 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: E Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1month 1.5 months 3 months Particle Size Distribution by Cascade 42 to 7366, 61 64, 77 61, 63 68, 65 59, 57 Impaction Fluticasone Propionate 67,69 61, 65 58, 64 63, 64 58, 55 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade 19 to 45 39, 34 35, 4431, 33 38, 36 31, 30 Impaction Fluticasone Propionate 39, 41 34, 36 30,33 35, 35 29, 28 Sum of stages 3-4 (μg per blister) Individual ParticleSize Distribution by Cascade 140 to 200 159, 154 159, 188 166, 172 172,162 177, 174 Impaction Fluticasone Propionate 161, 161 162, 165 170, 175170, 168 176, 177 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade <2 0, 0 0, 1 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F(μg per blister) Individual

TABLE 73 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH for 17 months withoverwrap Packed Batch Number: E Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1month 1.5 months Particle Size Distribution by Cascade  7 to 13 10, 1010, 10 (a) 10, 10 Impaction Salmeterol Sum of stages 9, 9 10, 10 10 9,10 1-5 (μg per blister) Individual Particle Size Distribution by Cascade3 to 8 5, 5 5, 5 (a) 5, 5 Impaction Salmeterol Sum of stages 4, 4 5, 5 44, 5 3-4 (μg per blister) Individual Particle Size Distribution byCascade 28 to 42 35, 37 35, 37 (a) 35, 36 Impaction Salmeterol Sum ofstages 36, 36 37, 35 36 35, 37 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.1, 0.1 0.0, 0.1 (a) 0.1, 0.1Impaction Salmeterol Sum of stages 0.1, 0.1 0.1, 0.1 0.0 0.1, 0.1 6, 7 &F (μg per blister) Individual

TABLE 74 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH for 17 months withoverwrap (cont'd) Packed Batch Number: E Storage condition 25° C./75% RHTesting Complete End of life Storage Time Test Specification Initial 2Weeks 1 month 1.5 months Particle Size Distribution by Cascade 42 to 7357, 56 58, 56 (a) 55, 57 Impaction Fluticasone Propionate 54, 54 57, 5557 52, 55 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade 19 to 45 29, 26 27, 26 (a) 28, 30 ImpactionFluticasone Propionate Sum of stages 3-4 (μg per blister) 25, 25 27, 2625 25, 27 Individual Particle Size Distribution by Cascade 140 to 200170, 182 171, 178 (a) 171, 178 Impaction Fluticasone Propionate 176, 175178, 168 182 174, 184 Sum of stages TP0 (μg per blister) IndividualParticle Size Distribution by Cascade <2 0, 0 0, 0 (a) 0, 0 ImpactionFluticasone Propionate 0, 0 0, 0 0 0, 0 Sum of stages 6, 7 & F (μg perblister) Individual

TABLE 75 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: F Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  7 to 13 13, 1212, 11 11, 11 11, 9 Impaction Salmeterol Sum of stages 13, 12 11, 11 11,11 10, 10 1-5 (μg per blister) 12, 12 Individual Particle SizeDistribution by Cascade 3 to 8 8, 7 7, 7 6, 6 5, 4 Impaction SalmeterolSum of stages 7, 7 6, 6 6, 6 5, 5 3-4 (μg per blister) 7, 7 IndividualParticle Size Distribution by Cascade 28 to 42 36, 35 36, 35 35, 35 36,34 Impaction Salmeterol Sum of stages 36, 35 36, 35 33, 31 36, 37 TP0(μg per blister) 36, 33 Individual Particle Size Distribution by CascadeNGT 0.5 0.1, 0.1 0.1, 0.1 0.0, 0.1 0.0, 0.0 Impaction Salmeterol Sum ofstages 0.1, 0.1 0.1, 0.1 0.1, 0.0 0.0, 0.0 6, 7 & F (μg per blister)0.1, 0.1 Individual

TABLE 76 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: F Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 Months 12Months 18 Months Particle Size Distribution by Cascade  7 to 13 13, 1211, 11 9, 10 9, 10 Impaction Salmeterol Sum of stages 13, 12 11, 12 9,10 10, 10 1-5 (μg per blister) 12, 12 Individual Particle SizeDistribution by Cascade 3 to 8 8, 7 6, 6 4, 4 4, 5 Impaction SalmeterolSum of stages 7, 7 5, 6 4, 5 5, 5 3-4 (μg per blister) 7, 7 IndividualParticle Size Distribution by Cascade Impaction Salmeterol Sum of stages28 to 42 36, 35 34, 36 35, 37 37, 35 TP0 (μg per blister) 36, 35 36, 3636, 38 35, 34 Individual 36, 33 Particle Size Distribution by CascadeImpaction Salmeterol Sum of stages NGT 0.5 0.1, 0.1 0.0, 0.0 0.0, 0.00.1, 0.1 6, 7 & F (μg per blister) 0.1, 0.1 0.0, 0.0 0.0, 0.0 0.1, 0.1Individual 0.1, 0.1

TABLE 77 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: F Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 42 to 73 76, 7067, 65 63, 61 62, 53 Impaction Fluticasone Propionate 73, 70 62, 61 64,63 61, 58 Sum of stages 1-5 (μg per blister) 68, 72 Individual ParticleSize Distribution by Cascade 19 to 45 46, 40 39, 39 34, 33 32, 26Impaction Fluticasone Propionate 43, 42 36, 35 36, 34 31, 28 Sum ofstages 3-4 (μg per blister) 39, 41 Individual Particle Size Distributionby Cascade 140 to 200 173, 170 176, 169 170, 171 175, 166 ImpactionFluticasone Propionate 170, 168 172, 172 163, 154 177, 180 Sum of stagesTP0 (μg per blister) 174, 159 Individual Particle Size Distribution byCascade <2 1, 0 0, 0 0, 0 0, 0 Impaction Fluticasone Propionate 1, 0 0,0 0, 0 0, 0 Sum of stages 6, 7 & F (μg per blister) 0, 0 Individual

TABLE 78 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: F Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 Months 12Months 18 Months Particle Size Distribution by Cascade 42 to 73 76, 7065, 65 50, 55 54, 55 Impaction Fluticasone Propionate 73, 70 63, 68 51,59 55, 57 Sum of stages 1-5 (μg per blister) 68, 72 Individual ParticleSize Distribution by Cascade 19 to 45 46, 40 33, 33 22, 26 25, 27Impaction Fluticasone Propionate 43, 42 31, 35 24, 27 27, 28 Sum ofstages 3-4 (μg per blister) 39, 41 Individual Particle Size Distributionby Cascade 140 to 200 173, 170 166, 178 172, 180 180, 170 ImpactionFluticasone Propionate 170, 168 175, 175 180, 187 172, 167 Sum of stagesTP0 (μg per blister) 174, 159 Individual Particle Size Distribution byCascade <2 1, 0 0, 0 0, 0 0, 0 Impaction Fluticasone Propionate 1, 0 0,0 0, 0 0, 0 Sum of stages 6, 7 & F (μg per blister) 0, 0 Individual

TABLE 79 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: F Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1313, 12 11, 12 11, 11 10, 12  9, 10 Impaction Salmeterol Sum of stages13, 12 11, 11 12, 11 11, 12 10, 11 1-5 (μg per blister) 12, 12Individual Particle Size Distribution by Cascade 3 to 8 8, 7 7, 7 6, 65, 6 5, 5 Impaction Salmeterol Sum of stages 7, 7 7, 7 7, 6 6, 6 5, 63-4 (μg per blister) 7, 7 Individual Particle Size Distribution byCascade 28 to 42 36, 35 36, 36 36, 36 32, 36 37, 37 Impaction SalmeterolSum of stages 36, 35 36, 36 35, 39 37, 36 36, 37 TP0 (μg per blister)36, 33 Individual Particle Size Distribution by Cascade NGT 0.5 0.1, 0.10.1, 0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages0.1, 0.1 0.1, 0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister)0.1, 0.1 Individual

TABLE 80 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: F Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade 42 to 7376, 70 65, 67 65, 64 59, 68 53, 60 Impaction Fluticasone Propionate 73,70 65, 65 66, 65 65, 67 59, 62 Sum of stages 1-5 (μg per blister) 68, 72Individual Particle Size Distribution by Cascade 19 to 45 46, 40 38, 3937, 37 31, 37 26, 31 Impaction Fluticasone Propionate 43, 42 37, 39 40,35 35, 37 30, 33 Sum of stages 3-4 (μg per blister) 39, 41 IndividualParticle Size Distribution by Cascade 140 to 200 173, 170 174, 173 175,174 152, 175 178, 180 Impaction Fluticasone Propionate 170, 168 172, 171168, 188 178, 173 176, 179 Sum of stages TP0 (μg per blister) 174, 159Individual Particle Size Distribution by Cascade <2 1, 0 0, 0 1, 0 0, 00, 0 Impaction Fluticasone Propionate 1, 0 0, 0 1, 0 0, 0 0, 0 Sum ofstages 6, 7 & F (μg per blister) 0, 0 Individual

TABLE 81 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH for 17 months withoverwrap Packed Batch Number: F Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade  7 to 13 10, 1010, 10 10, 10 10, 10 Impaction Salmeterol Sum of stages  9, 10 10, 1010, 10 10, 10 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 3 to 8 5, 5 5, 5 5, 5 5, 5 Impaction Salmeterol Sum of stages5, 5 5, 5 5, 5 5, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 36, 36 38, 37 37, 38 37, 37 ImpactionSalmeterol Sum of stages 34, 36 36, 37 35, 38 34, 36 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.0 0.1, 0.1 0.0, 0.0 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.1 0.1, 0.1 0.1, 0.0 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 82 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH for 17 months withoverwrap (cont'd) Packed Batch Number: F Storage condition 25° C./75% RHTesting Complete End of life Storage Time Test Specification Initial 2Weeks 1 Month 1.5 Months Particle Size Distribution by Cascade 42 to 7359, 57 55, 56 59, 58 55, 60 Impaction Fluticasone Propionate 53, 59 55,57 58, 59 57, 61 Sum of stages 1-5 (μg per blister) Individual ParticleSize Distribution by Cascade 19 to 45 30, 29 26, 28 28, 27 28, 30Impaction Fluticasone Propionate 27, 31 27, 28 29, 29 28, 30 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 140 to 200 177, 180 185, 183 183, 187 180, 182 ImpactionFluticasone Propionate 169, 180 179, 186 174, 184 170, 181 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by Cascade <20, 0 0, 0 0, 0 0, 0 Impaction Fluticasone Propionate 0, 0 0, 0 0, 0 0, 0Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 83 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: G Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  7 to 13 15, 1513, 12 13, 13 10, 12 Impaction Salmeterol Sum of stages 15, 16 12, 1312, 14 11, 12 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 3 to 8 9, 9 7, 7 7, 7 5, 6 Impaction Salmeterol Sum of stages9, 9 7, 8 6, 7 6, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 32, 33 32, 33 33, 36 30, 34 ImpactionSalmeterol Sum of stages 34, 35 32, 32 33, 35 31, 33 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.2 0.1, 0.1 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 84 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: G Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 18 months Particle Size Distribution by Cascade  7 to 13 15, 1512, 12 13, 14 11, 11 Impaction Salmeterol Sum of stages 15, 16 11, 1113, 14 11, 11 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 3 to 8 9, 9 6, 7 7, 7 6, 6 Impaction Salmeterol Sum of stages9, 9 6, 6 7, 7 6, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 32, 33 33, 32 33, 34 33, 33 ImpactionSalmeterol Sum of stages 34, 35 32, 33 34, 33 32, 34 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.0 0.1, 0.1 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.2 0.0, 0.0 0.1, 0.1 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 85 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: G Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 42 to 73 87, 8672, 68 77, 74 57, 69 Impaction Fluticasone Propionate 88, 92 70, 74 70,78 66, 72 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade 19 to 45 52, 48 42, 38 43, 40 29, 35 ImpactionFluticasone Propionate 53, 54 41, 44 37, 42 36, 37 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 140 to 200152, 157 153, 158 160, 174 150, 166 Impaction Fluticasone Propionate159, 165 150, 150 157, 168 150, 161 Sum of stages TP0 (μg per blister)Individual Particle Size Distribution by Cascade <2 1, 1 0, 0 0, 0 0, 0Impaction Fluticasone Propionate 1, 1 0, 0 0, 0 0, 0 Sum of stages 6, 7& F (μg per blister) Individual

TABLE 86 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: G Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 18 months Particle Size Distribution by Cascade 42 to 73 87, 8670, 70 75, 77 66, 66 Impaction Fluticasone Propionate 88, 92 63, 65 73,75 65, 66 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade 19 to 45 52, 48 37, 38 39, 42 33, 34 ImpactionFluticasone Propionate 53, 54 32, 33 38, 40 33, 33 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 140 to 200152, 157 157, 152 160, 163 161, 164 Impaction Fluticasone Propionate159, 165 155, 159 165, 162 158, 168 Sum of stages TP0 (μg per blister)Individual Particle Size Distribution by Cascade <2 1, 1 0, 0 0, 0 0, 0Impaction Fluticasone Propionate 1, 1 0, 0 0, 0 0, 0 Sum of stages 6, 7& F (μg per blister) Individual

TABLE 87 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: G Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1315, 15 13, 14 12, 13 14, 12 13, 11 Impaction Salmeterol Sum of stages15, 16 14, 13 12, 12 12, 12 11, 13 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 3 to 8 9, 9 6, 8 7, 7 8, 7 7, 6Impaction Salmeterol Sum of stages 9, 9 8, 7 7, 6 6, 7 6, 7 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 28 to 42 32,33 32, 33 32, 33 34, 32 32, 31 Impaction Salmeterol Sum of stages 34, 3535, 34 32, 33 32, 33 31, 33 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.1, 0.1 0.1, 0.1 0.1, 0.1 0.0, 0.00.0, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.2 0.1, 0.1 0.1, 0.10.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 88 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: G Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade 42 to 7387, 86 72, 82 67, 72 78, 70 76, 66 Impaction Fluticasone Propionate 88,92 81, 76 70, 68 68, 72 66, 73 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade 19 to 45 52, 48 37, 4638, 41 44, 40 42, 36 Impaction Fluticasone Propionate 53, 54 45, 41 40,37 35, 38 33, 40 Sum of stages 3-4 (μg per blister) Individual ParticleSize Distribution by Cascade 140 to 200 152, 157 155, 156 155, 157 163,152 156, 149 Impaction Fluticasone Propionate 159, 165 165, 160 155, 161156, 160 149, 160 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade <2 1, 1 0, 1 1, 0 0, 0 0, 0 ImpactionFluticasone Propionate 1, 1 1, 1 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F(μg per blister) Individual

TABLE 89 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH for 17 months withoverwrap Packed Batch Number: G Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade  7 to 13 12, 1211, 11 13, 12 11, 11 Impaction Salmeterol Sum of stages 11, 11 12, 1012, 11 10, 10 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 3 to 8 6, 6 6, 5 7, 6 6, 6 Impaction Salmeterol Sum of stages5, 5 6, 5 6, 6 4, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 33, 34 33, 33 34, 33 33, 32 ImpactionSalmeterol Sum of stages 33, 32 34, 32 34, 32 33, 34 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.1, 0.1 0.1, 0.1 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.1 0.1, 0.1 0.1, 0.1 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 90 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH for 17 months withoverwrap (cont'd) Packed Batch Number: G Storage condition 25° C./75% RHTesting Complete End of life Storage Time Test Specification Initial 2weeks 1 Month 1.5 Months Particle Size Distribution by Cascade 42 to 7371, 69 65, 63 73, 71 66, 62 Impaction Fluticasone Propionate 62, 62 67,61 68, 65 58, 61 Sum of stages 1-5 (μg per blister) Individual ParticleSize Distribution by Cascade 19 to 45 35, 33 33, 30 39, 37 36, 32Impaction Fluticasone Propionate 28, 29 32, 30 36, 33 26, 31 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 140 to 200 160, 166 156, 158 167, 161 162, 158 ImpactionFluticasone Propionate 161, 154 165, 155 165, 157 163, 166 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by Cascade <20, 0 0, 0 0, 0 0, 0 Impaction Fluticasone Propionate 0, 0 0, 0 0, 0 0, 0Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 91 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: H Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  7 to 13 11, 1010, 10 10, 9  9, 9 Impaction Salmeterol Sum of stages 12, 11 11, 10 10,10 9, 9 1-5 (μg per blister) Individual Particle Size Distribution byCascade 3 to 8 6, 6 6, 6 5, 5 5, 5 Impaction Salmeterol Sum of stages 7,6 6, 6 5, 5 5, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 38, 36 38, 37 39, 38 38, 37 ImpactionSalmeterol Sum of stages 37, 36 39, 38 38, 38 39, 37 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.0,0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 92 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: H Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 18 months Particle Size Distribution by Cascade  7 to 13 11, 109, 10 10, 10 10, 9  Impaction Salmeterol Sum of stages 12, 11 10, 10 10,10 9, 9 1-5 (μg per blister) Individual Particle Size Distribution byCascade 3 to 8 6, 6 5, 5 5, 5 5, 4 Impaction Salmeterol Sum of stages 7,6 5, 5 5, 5 4, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 38, 36 38, 36 38, 37 39, 37 ImpactionSalmeterol Sum of stages 37, 36 35, 35 38, 38 39, 33 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.0,0.1 0.0, 0.0 0.1, 0.1 0.1, 0.0 Impaction Salmeterol Sum of stages 0.1,0.1 0.0, 0.0 0.1, 0.1 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 93 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: H Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 42 to 73 61, 5957, 56 57, 55 53, 53 Impaction Fluticasone Propionate 66, 62 61, 58 59,57 55, 54 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade 19 to 45 35, 34 32, 32 30, 28 29, 28 ImpactionFluticasone Propionate 39, 34 34, 32 31, 29 28, 27 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 140 to 200181, 170 182, 180 185, 181 181, 179 Impaction Fluticasone Propionate175, 172 188, 185 181, 181 189, 181 Sum of stages TP0 (μg per blister)Individual Particle Size Distribution by Cascade <2 0, 0 0, 0 0, 0 0, 0Impaction Fluticasone Propionate 1, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7& F (μg per blister) Individual

TABLE 94 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoverwrap Packed Batch Number: H Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 18 months Particle Size Distribution by Cascade 42 to 73 61, 5955, 56 60, 61 55, 51 Impaction Fluticasone Propionate 66, 62 56, 58 60,59 50, 51 Sum of stages 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade 19 to 45 35, 34 27, 28 31, 32 27, 26 ImpactionFluticasone Propionate 39, 34 29, 30 31, 31 24, 27 Sum of stages 3-4 (μgper blister) Individual Particle Size Distribution by Cascade 140 to 200181, 170 182, 177 188, 182 188, 183 Impaction Fluticasone Propionate175, 172 172, 171 183, 183 193, 163 Sum of stages TP0 (μg per blister)Individual Particle Size Distribution by Cascade <2 0, 0 0, 0 0, 0 0, 0Impaction Fluticasone Propionate 1, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7& F (μg per blister) Individual

TABLE 95 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: H Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1311, 10 10, 10 10, 11 9, 9 9, 9 Impaction Salmeterol Sum of stages 12, 1110, 10 11, 10 10, 10 10, 9  1-5 (μg per blister) Individual ParticleSize Distribution by Cascade 3 to 8 6, 6 6, 6 5, 6 5, 5 4, 5 ImpactionSalmeterol Sum of stages 7, 6 6, 6 6, 5 5, 5 5, 4 3-4 (μg per blister)Individual Particle Size Distribution by Cascade 28 to 42 38, 36 37, 3536, 37 36, 37 39, 38 Impaction Salmeterol Sum of stages 37, 36 36, 3738, 37 38, 38 39, 37 TP0 (μg per blister) Individual Particle SizeDistribution by Cascade NGT 0.5 0.0, 0.1 0.1, 0.1 0.0, 0.0 0.0, 0.0 0.0,0.0 Impaction Salmeterol Sum of stages 0.1, 0.1 0.1, 0.1 0.0, 0.0 0.0,0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 96 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: H Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade 42 to 7361, 59 59, 58 61, 61 54, 54 54, 54 Impaction Fluticasone Propionate 66,62 59, 58 61, 59 57, 55 59, 53 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade 19 to 45 35, 34 33, 3432, 33 28, 28 26, 27 Impaction Fluticasone Propionate 39, 34 36, 34 32,32 30, 29 31, 26 Sum of stages 3-4 (μg per blister) Individual ParticleSize Distribution by Cascade 140 to 200 181, 170 180, 170 169, 175 175,179 189, 185 Impaction Fluticasone Propionate 175, 172 172, 177 180, 175183, 182 189, 181 Sum of stages TP0 (μg per blister) Individual ParticleSize Distribution by Cascade <2 0, 0 0, 1 0, 0 0, 0 0, 0 ImpactionFluticasone Propionate 1, 0 1, 0 0, 0 0, 0 0, 0 Sum of stages 6, 7 & F(μg per blister) Individual

TABLE 97 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH for 17 months withoverwrap Packed Batch Number: H Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade  7 to 13 9, 9 9,9 10, 10  9, 10 Impaction Salmeterol Sum of stages 10, 9  9, 9  9, 10 9,9 1-5 (μg per blister) Individual Particle Size Distribution by Cascade3 to 8 5, 5 5, 4 5, 5 4, 5 Impaction Salmeterol Sum of stages 5, 4 4, 55, 5 4, 5 3-4 (μg per blister) Individual Particle Size Distribution byCascade 28 to 42 37, 37 38, 38 36, 36 37, 38 Impaction Salmeterol Sum ofstages 36, 37 38, 37 37, 36 35, 36 TP0 (μg per blister) IndividualParticle Size Distribution by Cascade NGT 0.5 0.1, 0.1 0.1, 0.1 0.1, 0.10.1, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.1 0.1, 0.1 0.0, 0.10.2, 0.0 6, 7 & F (μg per blister) Individual

TABLE 98 Stability data for DISKUS ® 250/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH for 17 months withoverwrap (cont'd) Packed Batch Number: H Storage condition 25° C./75% RHTesting Complete End of life Storage Time Test Specification Initial 2weeks 1 Month 1.5 Months Particle Size Distribution by Cascade 42 to 7355, 54 54, 53 56, 55 51, 56 Impaction Fluticasone Propionate 57, 55 51,53 55, 57 51, 55 Sum of stages 1-5 (μg per blister) Individual ParticleSize Distribution by Cascade 19 to 45 27, 27 27, 26 29, 28 26, 28Impaction Fluticasone Propionate 28, 26 24, 27 27, 28 23, 27 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 140 to 200 179, 184 184, 184 177, 179 178, 184 ImpactionFluticasone Propionate 178, 183 188, 183 183, 178 175, 191 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by Cascade <20, 0 0, 0 0, 0 0, 0 Impaction Fluticasone Propionate 0, 0 0, 0 0, 0 1, 0Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 99 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: I Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  7 to 13 11, 1211, 11 10, 10 10, 10 Impaction Salmeterol Sum of stages 12, 11 11, 1010, 10  9, 10 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 4 to 8 7, 7 6, 6 5, 5 5, 5 Impaction Salmeterol Sum of stages7, 7 6, 6 6, 6 5, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 34, 35 31, 36 36, 35 33, 36 ImpactionSalmeterol Sum of stages 35, 33 33, 34 36, 36 33, 33 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.0 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.1 0.0, 0.0 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 100 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: I Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 Months 12Months 18 Months Particle Size Distribution by Cascade  7 to 13 11, 1210, 10 10, 9  9, 9 Impaction Salmeterol Sum of stages 12, 11 10, 10 8, 99, 9 1-5 (μg per blister) Individual Particle Size Distribution byCascade 4 to 8 7, 7 5, 5 5, 4 5, 4 Impaction Salmeterol Sum of stages 7,7 5, 6 4, 4 5, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 34, 35 35, 34 37, 34 36, 34 ImpactionSalmeterol Sum of stages 35, 33 37, 37 32, 36 34, 35 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.1, 0.0 0.0, 0.0 0.0, 0.1 Impaction Salmeterol Sum of stages 0.1,0.1 0.0, 0.0 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 101 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: I Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  96 to 150 127,130 119, 122 112, 111 110, 114 Impaction Fluticasone Propionate 129, 125121, 112 117, 116 105, 116 Sum of stages 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 43 to 92 75, 76 70, 71 60, 59 60,61 Impaction Fluticasone Propionate 77, 75 71, 62 64, 64 55, 63 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 290 to 400 325, 339 301, 354 349, 346 326, 346 ImpactionFluticasone Propionate 337, 322 326, 333 350, 349 325, 319 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 1, 0 1, 1 Impaction Fluticasone Propionate 1, 1 1, 1 1,1 1, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 102 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: I Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 Months 12Months 18 Months Particle Size Distribution by Cascade  96 to 150 127,130 110, 110 110, 96  100, 95  Impaction Fluticasone Propionate 129, 125109, 114 91, 99 106, 104 Sum of stages 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 43 to 92 75, 76 59, 60 60, 50 51,50 Impaction Fluticasone Propionate 77, 75 59, 62 48, 48 57, 56 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 290 to 400 325, 339 342, 332 360, 337 351, 335 ImpactionFluticasone Propionate 337, 322 364, 364 313, 348 342, 349 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 0, 0 1, 1 Impaction Fluticasone Propionate 1, 1 1, 1 0,0 1, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 103 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: I Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1311, 12 11, 11 10, 11 10, 11 10, 10 Impaction Salmeterol Sum of stages12, 11 12, 11 11, 11 11, 11 10, 9  1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 4 to 8 7, 7 6, 6 6, 7 6, 6 6, 6Impaction Salmeterol Sum of stages 7, 7 7, 6 6, 6 6, 6 5, 5 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 28 to 42 34,35 37, 37 35, 36 34, 34 36, 34 Impaction Salmeterol Sum of stages 35, 3337, 35 36, 36 35, 35 35, 33 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.1, 0.1 0.1, 0.1 0.0, 0.0 0.0, 0.00.0, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.1 0.1, 0.1 0.0, 0.00.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 104 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: I Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  96 to150 127, 130 127, 125 116, 128 114, 124 118, 113 Impaction FluticasonePropionate 129, 125 131, 117 119, 127 125, 118 113, 105 Sum of stages1-5 (μg per blister) Individual Particle Size Distribution by Cascade 43to 92 75, 76 70, 68 66, 73 67, 72 65, 64 Impaction FluticasonePropionate 77, 75 73, 66 69, 72 71, 67 62, 56 Sum of stages 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 290 to 400325, 339 355, 362 336, 352 326, 324 345, 332 Impaction FluticasonePropionate 337, 322 358, 341 346, 348 337, 345 344, 322 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 1, 1 1, 1 1, 1 Impaction Fluticasone Propionate 1, 1 1,1 1, 1 1, 1 1, 0 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 105 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 17months Packed Batch Number: I Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade  7 to 13 10, 9 9, 9 10, 10 9, 9 Impaction Salmeterol Sum of stages 9, 9 10, 10 10, 9  9, 10 1-5 (μg per blister) Individual Particle Size Distribution byCascade 4 to 8 6, 4 5, 5 5, 5 4, 5 Impaction Salmeterol Sum of stages 5,5 5, 5 5, 5 5, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 35, 38 37, 36 36, 36 35, 34 ImpactionSalmeterol Sum of stages 36, 36 37, 38 35, 34 35, 36 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.0,0.0 0.1, 0.0 0.1, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.0,0.0 0.1, 0.1 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 106 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 17months (cont'd) Packed Batch Number: I Storage condition 25° C./75% RHTesting Complete End of life Storage Time Test Specification Initial 2Weeks 1 Month 1.5 Months Particle Size Distribution by Cascade  96 to150 107, 101 101, 101 115, 108 105, 102 Impaction Fluticasone Propionate103, 105 107, 112 108, 104 101, 108 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade 43 to 92 70, 50 54, 5162, 56 50, 55 Impaction Fluticasone Propionate 51, 53 55, 59 56, 55 52,57 Sum of stages 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 290 to 400 344, 375 361, 355 359, 353 344, 334Impaction Fluticasone Propionate 351, 359 369, 375 347, 341 344, 353 Sumof stages TP0 (μg per blister) Individual Particle Size Distribution byCascade NGT 2 1, 0 1, 1 1, 1 1, 1 Impaction Fluticasone Propionate 1, 11, 1 1, 1 1, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 107 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: J Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  7 to 13 11, 1110, 11 10, 11  9, 10 Impaction Salmeterol Sum of stages 12, 11 10, 1011, 10 10, 10 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 4 to 8 7, 7 6, 6 5, 6 5, 5 Impaction Salmeterol Sum of stages7, 6 6, 6 6, 5 5, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 35, 36 35, 34 36, 36 36, 37 ImpactionSalmeterol Sum of stages 35, 32 35, 34 36, 36 36, 35 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.0 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.0 0.0, 0.0 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 108 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: J Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 Months 12Months 18 Months Particle Size Distribution by Cascade  7 to 13 11, 1110, 10 10, 10 10, 10 Impaction Salmeterol Sum of stages 12, 11 9, 9 10,10 11, 9  1-5 (μg per blister) Individual Particle Size Distribution byCascade 4 to 8 7, 7 5, 5 6, 5 6, 5 Impaction Salmeterol Sum of stages 7,6 5, 5 6, 5 6, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 35, 36 35, 33 38, 37 35, 35 ImpactionSalmeterol Sum of stages 35, 32 36, 35 37, 37 36, 34 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.0 0.0, 0.0 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.0 0.0, 0.0 0.0, 0.0 0.1, 0.0 6, 7 & F (μg per blister) Individual

TABLE 109 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: J Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 96 to 150 125, 124114, 118 113, 124 105, 108 Impaction Fluticasone Propionate 127, 116114, 113 119, 115 110, 109 Sum of stages 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 43 to 92 75, 77 65, 70 61, 70 54,56 Impaction Fluticasone Propionate 77, 70 65, 67 65, 60 58, 58 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 290 to 400 336, 344 338, 329 354, 350 363, 369 ImpactionFluticasone Propionate 344, 309 340, 325 359, 358 352, 341 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 1, 1 1, 0 Impaction Fluticasone Propionate 1, 1 1, 1 1,1 0, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 110 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: J Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 months 12months 18 months Particle Size Distribution by Cascade  96 to 150 125,124 111, 108 113, 113 113, 108 Impaction Fluticasone Propionate 127, 116103, 106 115, 114 117, 105 Sum of stages 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 43 to 92 75, 77 59, 60 61, 61 64,58 Impaction Fluticasone Propionate 77, 70 55, 57 62, 59 64, 56 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 290 to 400 336, 344 343, 330 363, 358 350, 349 ImpactionFluticasone Propionate 344, 309 353, 342 361, 367 355, 344 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 1, 1 1, 1 Impaction Fluticasone Propionate 1, 1 1, 1 1,1 1, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 111 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: J Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1311, 11 11, 11 11, 11 11, 11  9, 10 Impaction Salmeterol Sum of stages12, 11 11, 11 11, 11 11, 10 10, 11 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 4 to 8 7, 7 6, 6 6, 7 7, 7 5, 6Impaction Salmeterol Sum of stages 7, 6 6, 6 6, 6 7, 6 5, 6 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 28 to 42 35,36 35, 36 34, 36 34, 34 35, 36 Impaction Salmeterol Sum of stages 35, 3235, 35 36, 34 32, 34 35, 37 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.1, 0.1 0.1, 0.1 0.0, 0.0 0.0, 0.00.0, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.0 0.1, 0.1 0.0, 0.00.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 112 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: J Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  96 to150 125, 124 121, 121 118, 123 124, 127 103, 116 Impaction FluticasonePropionate 127, 116 120, 120 122, 118 123, 115 108, 117 Sum of stages1-5 (μg per blister) Individual Particle Size Distribution by Cascade 43to 92 75, 77 68, 67 71, 73 72, 75 54, 66 Impaction FluticasonePropionate 77, 70 69, 66 71, 70 73, 64 60, 66 Sum of stages 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 290 to 400336, 344 339, 348 325, 345 334, 331 341, 353 Impaction FluticasonePropionate 344, 309 337, 343 346, 331 314, 332 341, 361 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 1, 1 1, 1 1, 1 Impaction Fluticasone Propionate 1, 1 1,1 1, 1 1, 1 1, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 113 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 17months Packed Batch Number: J Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade  7 to 13  9, 1010, 10 10, 10 10, 11 Impaction Salmeterol Sum of stages 10, 10 10, 10 9, 10 10, 10 1-5 (μg per blister) Individual Particle Size Distributionby Cascade 4 to 8 4, 6 5, 5 5, 6 6, 6 Impaction Salmeterol Sum of stages5, 5 5, 5 5, 5 5, 6 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 36, 36 36, 35 35, 35 38, 37 ImpactionSalmeterol Sum of stages 35, 36 37, 35 34, 36 34, 35 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.0,0.1 0.1, 0.1 0.0, 0.1 0.1, 0.1 Impaction Salmeterol Sum of stages 0.1,0.1 0.0, 0.1 0.0, 0.1 0.0, 0.1 6, 7 & F (μg per blister) Individual

TABLE 114 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 17months (cont'd) Packed Batch Number: J Storage condition 25° C./75% RHTesting Complete End of life Storage Time Test Specification Initial 2Weeks 1 Month 1.5 Months Particle Size Distribution by Cascade  96 to150 100, 115 114, 105 107, 114 108, 117 Impaction Fluticasone Propionate108, 115 115, 107  99, 112 116, 114 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade 43 to 92 49, 61 58, 5357, 63 61, 63 Impaction Fluticasone Propionate 57, 59 60, 56 52, 61 60,64 Sum of stages 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 290 to 400 346, 359 355, 341 344, 348 367, 365Impaction Fluticasone Propionate 341, 360 366, 348 338, 357 340, 353 Sumof stages TP0 (μg per blister) Individual Particle Size Distribution byCascade NGT 2 0, 1 1, 1 1, 1 1, 1 Impaction Fluticasone Propionate 1, 11, 1 1, 1 1, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 115 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: K Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade 7 to 13 11, 12 11,11 9, 11 10 11 Impaction Salmeterol Sum of stages 12, 12 11, 11 10, 1011, 9 1-5 (μg per blister) Individual Particle Size Distribution byCascade 4 to 8 7, 7 6, 6 5, 6 6, 6 Impaction Salmeterol Sum of stages 8,7 6, 6 5, 6 6, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 36, 37 35, 37 34, 36 36, 37 ImpactionSalmeterol Sum of stages 37, 39 36, 36 35, 38 37, 34 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.0 0.0, 0.0 0.0, 0.0 Impaction Salmeterol Sum of stages 0.1,0.1 0.0, 0.0 0.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 116 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: K Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 Months 12Months 18 Months Particle Size Distribution by Cascade  7 to 13 11, 1210, 10 10, 8  9, 9 Impaction Salmeterol Sum of stages 12, 12 10, 9  10,9  10, 9  1-5 (μg per blister) Individual Particle Size Distribution byCascade 4 to 8 7, 7 6, 5 5, 4 5, 5 Impaction Salmeterol Sum of stages 8,7 6, 5 5, 4 5, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 36, 37 36, 38 36, 34 36, 36 ImpactionSalmeterol Sum of stages 37, 39 35, 36 38, 36 36, 37 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.1 0.0, 0.0 0.0, 0.0 0.1, 0.0 Impaction Salmeterol Sum of stages 0.1,0.1 0.0, 0.0 0.0, 0.0 0.1, 0.0 6, 7 & F (μg per blister) Individual

TABLE 117 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: K Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  96 to 150 124,132 118, 124 104, 120 113, 118 Impaction Fluticasone Propionate 138, 136120, 119 113, 117 118, 104 Sum of stages 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 43 to 92 76, 80 69, 71 54, 67 64,65 Impaction Fluticasone Propionate 83, 81 70, 68 61, 63 66, 57 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 290 to 400 344, 353 356, 363 334, 350 353, 361 ImpactionFluticasone Propionate 352, 371 353, 349 340, 365 367, 337 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 0, 1 1, 0 Impaction Fluticasone Propionate 1, 1 1, 1 1,1 1, 0 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 118 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: K Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 Months 12Months 18 Months Particle Size Distribution by Cascade  96 to 150 124,132 115, 113 107, 85  103, 103 Impaction Fluticasone Propionate 138, 136111, 106 107, 94  112, 105 Sum of stages 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 43 to 92 76, 80 67, 60 55, 41 57,52 Impaction Fluticasone Propionate 83, 81 64, 55 55, 48 60, 56 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 290 to 400 344, 353 351, 368 356, 340 350, 355 ImpactionFluticasone Propionate 352, 371 342, 361 382, 359 356, 365 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 0, 0 1, 0 Impaction Fluticasone Propionate 1, 1 1, 1 0,0 1, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 119 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: K Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1311, 12 10, 10 11, 11 11, 10 10, 11 Impaction Salmeterol Sum of stages12, 12 12, 10 11, 11 11, 11 11, 11 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 4 to 8 7, 7 6, 6 6, 6 6, 5 6, 6Impaction Salmeterol Sum of stages 8, 7 7, 6 6, 6 6, 7 6, 6 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 28 to 42 36,37 34, 35 35, 36 35, 34 32, 35 Impaction Salmeterol Sum of stages 37, 3937, 36 35, 35 32, 38 35, 35 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.1, 0.1 0.1, 0.1 0.0, 0.0 0.0, 0.00.0, 0.0 Impaction Salmeterol Sum of stages 0.1, 0.1 0.1, 0.0 0.0, 0.00.0, 0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 120 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: K Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  96 to150 124, 132 111, 114 117, 121 118, 108 113, 121 Impaction FluticasonePropionate 138, 136 129, 111 120, 120 125, 126 118, 122 Sum of stages1-5 (μg per blister) Individual Particle Size Distribution by Cascade 42to 93 76, 80 66, 68 69, 69 66, 58 65, 68 Impaction FluticasonePropionate 83, 81 77, 63 70, 71 72, 72 65, 70 Sum of stages 3-4 (μg perblister) Individual Particle Size Distribution by Cascade 290 to 400344, 353 330, 340 339, 353 340, 329 315, 343 Impaction FluticasonePropionate 352, 371 354, 345 339, 344 310, 355 345, 340 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 1, 1 1, 1 1, 1 Impaction Fluticasone Propionate 1, 1 1,1 1, 1 1, 1 1, 2 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 121 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 17months Packed Batch Number: K Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade  7 to 13 10, 109, 9 11, 10 10, 10 Impaction Salmeterol Sum of stages 10, 9  9, 9 10, 1010, 9  1-5 (μg per blister) Individual Particle Size Distribution byCascade 4 to 8 5, 5 5, 5 6, 5 6, 5 Impaction Salmeterol Sum of stages 5,5 5, 5 5, 5 5, 5 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 28 to 42 38, 35 35, 36 37, 35 37, 36 ImpactionSalmeterol Sum of stages 37, 36 34, 34 36, 35 36, 35 TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 0.5 0.1,0.0 0.0, 0.1 0.1, 0.1 0.0, 0.0 Impaction Salmeterol Sum of stages 0.0,0.0 0.0, 0.1 0.0, 0.1 0.1, 0.1 6, 7 & F (μg per blister) Individual

TABLE 122 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 17months (cont'd) Packed Batch Number: K Storage condition 25° C./75% RHTesting Complete End of life Storage Time Test Specification Initial 2Weeks 1 Month 1.5 Months Particle Size Distribution by Cascade  96 to150 109, 111 100, 106 119, 109 108, 110 Impaction Fluticasone Propionate109, 105 103, 102 110, 109 111, 103 Sum of stages 1-5 (μg per blister)Individual Particle Size Distribution by Cascade 43 to 92 58, 59 53, 5662, 56 60, 57 Impaction Fluticasone Propionate 58, 54 55, 55 61, 61 58,56 Sum of stages 3-4 (μg per blister) Individual Particle SizeDistribution by Cascade 290 to 400 373, 349 351, 361 369, 348 365, 352Impaction Fluticasone Propionate 367, 361 343, 340 357, 351 352, 347 Sumof stages TP0 (μg per blister) Individual Particle Size Distribution byCascade NGT 2 1, 0 1, 1 1, 1 1, 1 Impaction Fluticasone Propionate 1, 01, 1 1, 1 1, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 123 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: L Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  7 to 13 10, 10 8,8 8, 8 9, 8 Impaction Salmeterol Sum of stages 10, 10 9, 9 8, 8 8, 8 1-5(μg per blister) Individual Particle Size Distribution by Cascade 4 to 86, 6 5, 4 4, 4 5, 4 Impaction Salmeterol Sum of stages 5, 6 5, 5 4, 4 4,4 3-4 (μg per blister) Individual Particle Size Distribution by Cascade28 to 42 36, 34 36, 36 36, 37 36, 36 Impaction Salmeterol Sum of stages36, 35 37, 37 35, 36 36, 37 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.0, 0.0 0.0, 0.0 0.0, 0.0 0.0, 0.0Impaction Salmeterol Sum of stages 0.0, 0.0 0.0, 0.0 0.0, 0.0 0.0, 0.06, 7 & F (μg per blister) Individual

TABLE 124 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: L Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 Months 12Months 18 Months Particle Size Distribution by Cascade  7 to 13 10, 1010, 9  8, 6 9, 9 Impaction Salmeterol Sum of stages 10, 10 9, 9 7, 7 8,8 1-5 (μg per blister) Individual Particle Size Distribution by Cascade4 to 8 6, 6 5, 5 4, 3 5, 5 Impaction Salmeterol Sum of stages 5, 6 5, 53, 4 5, 5 3-4 (μg per blister) Individual Particle Size Distribution byCascade 28 to 42 36, 34 36, 37 36, 35 36, 38 Impaction Salmeterol Sum ofstages 36, 35 35, 36 35, 36 34, 35 TP0 (μg per blister) IndividualParticle Size Distribution by Cascade NGT 0.5 0.0, 0.0 0.0, 0.0 0.0, 0.00.1, 0.1 Impaction Salmeterol Sum of stages 0.0, 0.0 0.0, 0.0 0.0, 0.00.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 125 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: L Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 1 Month 3Months 6 Months Particle Size Distribution by Cascade  96 to 150 116,115 94, 90 90, 93 104, 94  Impaction Fluticasone Propionate 105, 108101, 104 89, 92 88, 93 Sum of stages 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 43 to 92 67, 70 52, 48 46, 49 56,49 Impaction Fluticasone Propionate 60, 64 54, 59 47, 50 44, 48 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 290 to 400 355, 337 350, 355 352, 367 356, 354 ImpactionFluticasone Propionate 348, 343 358, 360 342, 358 357, 358 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 0 0, 0 0, 0 Impaction Fluticasone Propionate 1, 1 0, 1 0,0 0, 0 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 126 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoverwrap Packed Batch Number: L Storage condition 25° C./60% RH TestingComplete End of life Storage Time Test Specification Initial 9 Months 12Months 18 Months Particle Size Distribution by Cascade  96 to 150 116,115 109, 96  92, 71 97, 97 Impaction Fluticasone Propionate 105, 108 96, 100 79, 83 95, 94 Sum of stages 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 43 to 92 67, 70 57, 51 47, 32 53,54 Impaction Fluticasone Propionate 60, 64 52, 52 38, 40 52, 50 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 290 to 400 355, 337 357, 361 360, 354 360, 381 ImpactionFluticasone Propionate 348, 343 345, 355 347, 363 345, 353 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 1, 1 1, 1 0, 0 1, 1 Impaction Fluticasone Propionate 1, 1 0, 1 0,0 1, 1 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 127 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: L Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  7 to 1310, 10 10, 9  9, 9 10, 9  8, 7 Impaction Salmeterol Sum of stages 10, 109, 9 8, 9 10, 10 9, 8 1-5 (μg per blister) Individual Particle SizeDistribution by Cascade 4 to 8 6, 6 6, 5 5, 5 6, 5 4, 4 ImpactionSalmeterol Sum of stages 5, 6 5, 5 5, 5 5, 5 5, 5 3-4 (μg per blister)Individual Particle Size Distribution by Cascade 28 to 42 36, 34 38, 3637, 36 36, 34 36, 36 Impaction Salmeterol Sum of stages 36, 35 35, 3736, 37 35, 36 36, 36 TP0 (μg per blister) Individual Particle SizeDistribution by Cascade NGT 0.5 0.0, 0.0 0.1, 0.1 0.0, 0.0 0.0, 0.0 0.0,0.0 Impaction Salmeterol Sum of stages 0.0, 0.0 0.0, 0.0 0.0, 0.0 0.0,0.0 0.0, 0.0 6, 7 & F (μg per blister) Individual

TABLE 128 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Packed Batch Number: L Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months 3 Months Particle Size Distribution by Cascade  96 to150 116, 115 113, 102 97, 99 109, 106 91, 82 Impaction FluticasonePropionate 105, 108 101, 97   94, 104 109, 107 97, 94 Sum of stages 1-5(μg per blister) Individual Particle Size Distribution by Cascade 43 to92 67, 70 63, 60 53, 55 62, 59 48, 46 Impaction Fluticasone Propionate60, 64 58, 56 53, 59 61, 61 52, 51 Sum of stages 3-4 (μg per blister)Individual Particle Size Distribution by Cascade 290 to 400 355, 337371, 346 359, 350 349, 333 354, 351 Impaction Fluticasone Propionate348, 343 345, 356 345, 357 340, 355 356, 356 Sum of stages TP0 (μg perblister) Individual Particle Size Distribution by Cascade NGT 2 1, 1 1,1 0, 1 1, 1 0, 1 Impaction Fluticasone Propionate 1, 1 1, 1 0, 1 1, 1 0,0 Sum of stages 6, 7 & F (μg per blister) Individual

TABLE 129 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 17months Packed Batch Number: L Storage condition 25° C./75% RH TestingComplete End of life Storage Time Test Specification Initial 2 Weeks 1Month 1.5 Months Particle Size Distribution by Cascade  7 to 13 8, 7 8,9 9, 7 9, 9 Impaction Salmeterol Sum of stages 8, 8 7, 8 8, 8 9, 9 1-5(μg per blister) Individual Particle Size Distribution by Cascade 4 to 84, 4 4, 4 4, 4 5, 4 Impaction Salmeterol Sum of stages 4, 4 4, 4 4, 4 4,4 3-4 (μg per blister) Individual Particle Size Distribution by Cascade28 to 42 36, 35 35, 36 34, 35 36, 37 Impaction Salmeterol Sum of stages38, 36 34, 35 37, 35 36, 37 TP0 (μg per blister) Individual ParticleSize Distribution by Cascade NGT 0.5 0.0, 0.0 0.0, 0.0 0.0, 0.0 0.0, 0.0Impaction Salmeterol Sum of stages 0.0, 0.0 0.0, 0.0 0.0, 0.0 0.0, 0.06, 7 & F (μg per blister) Individual

TABLE 130 Stability data for DISKUS ® 500/50 μg 60 Dose Product withoutoverwrap Samples previously stored at 25° C./60% RH with overwrap for 17months (cont'd) Packed Batch Number: L Storage condition 25° C./75% RHTesting Complete End of life Storage Time Test Specification Initial 2Weeks 1 Month 1.5 Months Particle Size Distribution by Cascade  96 to150 86, 83 86, 96 96, 83 95, 98 Impaction Fluticasone Propionate 94, 9179, 92 85, 86 97, 96 Sum of stages 1-5 (μg per blister) IndividualParticle Size Distribution by Cascade 43 to 92 44, 43 46, 49 49, 43 51,47 Impaction Fluticasone Propionate 49, 46 42, 50 43, 45 48, 49 Sum ofstages 3-4 (μg per blister) Individual Particle Size Distribution byCascade 290 to 400 356, 354 350, 364 337, 348 358, 371 ImpactionFluticasone Propionate 353, 359 340, 349 371, 347 359, 372 Sum of stagesTP0 (μg per blister) Individual Particle Size Distribution by CascadeNGT 2 0, 0 1, 1 0, 0 0, 0 Impaction Fluticasone Propionate 0, 0 0, 0 0,0 0, 1 Sum of stages 6, 7 & F (μg per blister) Individual

The invention has been described in reference to the embodiments setforth above. It should be appreciated that such embodiments are forillustrative purposes only, and do not limit the scope of the inventionas defined by the claims.

1. A process for forming lactose suitable for use in a pharmaceuticalformulation, said process comprising: providing a plurality of lactoseparticles containing no more than 10% w/w of lactose particles having avolume average particle size of about 70 microns or less; milling theplurality of lactose particles to yield a plurality of milled lactoseparticles with an average particle size, (D50), ranging from about 50microns to about 100 microns; and classifying said plurality of milledlactose particles into at least two fractions comprising a fine fractionand a coarse fraction wherein the fine fraction has an average particlesize, (D50), ranging from about 3 microns to about 50 microns, and thecoarse fraction has an average particle size, (D50), ranging from about40 microns to about 250 microns.
 2. The process according to claim 1,wherein said step of providing a plurality of lactose particlescontaining no more than 10% w/w of lactose particles having a volumeaverage particle size of about 70 microns or less comprises obtainingthe plurality of lactose particles from a crystallization process. 3.The process according to claim 1, wherein said step of providing aplurality of lactose particles containing no more than 10% w/w oflactose particles having a volume average particle size of about 70microns or less comprises obtaining said plurality of lactose particlesby sieving a source of lactose to produce the plurality of lactoseparticles containing no more than 10% w/w of lactose particles having avolume average particle size of about 70 microns or less.
 4. The processaccording to claim 1, wherein said step of providing a plurality oflactose particles containing no more than 10% w/w of lactose particleshaving a volume average particle size of about 70 microns or lesscomprises obtaining said plurality of lactose particles by classifying asource of lactose into two fractions comprising a fine fraction and saidplurality of lactose particles containing no more than 10% w/w oflactose particles having a volume average particle size of about 70microns or less.
 5. The process according to claim 1, wherein thelactose is selected from the group consisting of anhydrous lactose,lactose monohydrate, and combinations thereof.
 6. The process accordingto claim 1, further comprising combining at least one medicament with alactose composition to form a pharmaceutical formulation, the lactosecomposition comprising from 0 to 100 percent by weight of the coarsefraction and from 0 to 100 percent by weight of the fine fraction. 7.The process according to claim 1, further comprising: combining at leasta portion of the coarse fraction with at least a portion of the finefraction to form a lactose composition; and combining the lactosecomposition with at least one medicament to form a pharmaceuticalformulation.
 8. The process according to claim 1, further comprisingcombining: (i) from 0 to 100 percent by weight of the coarse fraction,(ii) from 0 to 100 percent by weight of the fine fraction, and (iii) atleast one medicament to form a pharmaceutical formulation.
 9. Theprocess according to claim 6, wherein the pharmaceutical formulation isa dry powder pharmaceutical formulation suitable for inhalation.
 10. Theprocess according to claim 6, wherein said at least one medicament isselected from the group consisting of analgesics, anginal preparations,antiinfectives, antihistamines, anti-inflammatories, antitussives,bronchodilators, diuretics, anticholinergics, hormones, xanthines,therapeutic proteins and peptides, salts thereof, esters thereof,solvates thereof, and combinations thereof.
 11. The process according toclaim 6, wherein the at least one medicament comprises at least one betaagonist.
 12. The process according to claim 11, wherein the at least onebeta agonist is selected from the group consisting of salbutamol,terbutaline, salmeterol, bitolterol, formoterol, esters thereof,solvates thereof, salts thereof, and combinations thereof.
 13. Theprocess according to claim 11, wherein the at least one beta agonistcomprises salmeterol xinafoate.
 14. The process according to claim 11,wherein the at least one beta agonist comprises salbutamol sulphate. 15.The process according to claim 6, wherein the at least one medicamentcomprises at least one anti-inflammatory steroid.
 16. The processaccording to claim 15, wherein the at least one anti-inflammatorysteroid is selected from the group consisting of mometasone,beclomethasone, budesonide, fluticasone, dexamethasone, flunisolide,triamcinolone, esters thereof, solvates thereof, salts thereof, andcombinations thereof.
 17. The process according to claim 15, wherein theat least one anti-inflammatory steroid comprises fluticasone propionate.18. The process according to claim 6, wherein the at least onemedicament comprises at least one beta agonist and at least oneanti-inflammatory steroid.
 19. The process according to claim 18,wherein the at least one beta agonist comprises salmeterol xinafoate andthe at least one anti-inflammatory steroid comprises fluticasonepropionate.
 20. The process according to claim 6, wherein the at leastone medicament is selected from the group consisting of beclomethasone,fluticasone, flunisolide, budesonide, rofleponide, mometasone,triamcinolone, noscapine, albuterol, salmeterol, ephedrine, adrenaline,fenoterol, formoterol, isoprenaline, metaproterenol, terbutaline,tiotropium, ipatropium, phenylephrine, phenylpropanolamine, pirbuterol,reproterol, rimiterol, isoetharine, tulobuterol,(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]methyl]benzenemethanol,esters thereof, solvates thereof, salts thereof, and combinationsthereof.
 21. The process according to claim 6, wherein the at least onemedicament is selected from the group consisting of albuterol sulphate,salmeterol xinafoate, fluticasone propionate, beclomethasonedipropionate, and combinations thereof.
 22. The process according toclaim 6, wherein said pharmaceutical formulation further comprises atleast one additional excipient.